Serotonin receptor modulators

ABSTRACT

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of US provisional patent applicationSer. No. 61/109,903, filed Oct. 30, 2008.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are serotoninreceptor modulators. More particularly, there is provided by the presentinvention certain compounds that are serotonin receptor modulatorsuseful for the treatment of disease states mediated by serotoninreceptor activity.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmittereliciting effects via a multiplicity of receptors. To date, at leastfifteen different 5-HT receptors have been identified, largely as theresult of cDNA cloning. These receptors have been grouped into sevenfamilies (5-HT₁ through 5-HT₇) (Hoyer, D. et al. Pharmacol. Biochem.Behav., 2002, 71, 533-554).

Fourteen of the fifteen cloned 5-HT receptors are expressed in thebrain. 5-HT is implicated in many disease states, particularlyconditions of the central nervous system including; depression, anxiety,schizophrenia, eating disorders, obsessive compulsive disorder, learningand memory dysfunction, migraine, chronic pain, sensory perception,motor activity, temperature regulation, nociception, sexual behavior,hormone secretion, and cognition.

The identification of multiple 5-HT receptors has provided theopportunity to characterize existing therapeutic agents thought to actvia the serotonergic system. Consequently, this has led to therealization that many drugs have non-selective properties (Roth, B. L.et al., Neuroscientist, 2000, 6(4), 252-262). For example, theantipsychotic drugs, clozapine, chlorpromazine, haloperidol andolanzapine exhibit affinities for multiple serotonin receptors inaddition to other families of receptors. Similar behavior has been notedfor antidepressants including imipramine, nortriptaline, fluoxetine andsertraline. Similarly, the anti-migraine agent sumatriptan exhibits highaffinity for several serotonin receptors. While the lack of selectivityoften contributes to a favorable therapeutic outcome, it can also causeundesirable and dose-limiting side effects (Stahl, S. M., EssentialPsychopharmacology, 2^(nd) ed., Cambridge University Press, Cambridge,U.K., 2000). For example, the inhibition of serotonin and norepinephrineuptake together with 5-HT₂ receptor blockade is responsible for thetherapeutic effects of the tricyclic antidepressants. In contrast, theirblockade of histamine H₁, muscarinic and alpha-adrenergic receptors canlead to sedation, blurred vision and orthostatic hypertensionrespectively. Likewise, the atypical antipsychotics, includingolanzapine and clozapine, are considered to have positive therapeuticeffects attributable to their actions at 5-HT₂, D₂ and 5-HT₇ receptors.Conversely, their side effect liability is due to their affinities for arange of dopaminergic, serotonergic and adrenergic receptors.

Elucidating selective ligands has the potential to ameliorate untowardpharmacologies and provide novel efficacious therapies. Moreimportantly, the ability to obtain compounds which portray receptorselectivity provides the prospect to target distinct therapeuticmechanisms and improve clinical responses with a single drug.Consequently, there remains a need for potent serotonin receptormodulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain compounds have now been found to have 5HT-modulating activity,in particular 5HT₇ and/or serotonin transporter modulating activity. Inparticular, the invention is directed to the general and preferredembodiments defined, respectively, and by the independent and dependentclaims appended hereto, which are incorporated by reference herein.

Thus, in one general aspect, the invention relates to compounds ofFormula (I):

whereinR¹ is —H₁, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl;m is 1, 2 or 3,n is 1 or 2, with the proviso that if m is 2, then n is not 1;R² and R³ are each independently —H or —C₁₋₄alkyl;R⁴ is —H, F, C₁₋₄alkyl, or R⁴ is —OH when L is —CH₂—, —CF₂—, or —CHF—,—OCH₂—, or —OCH(CH₃)—;

L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or —CHF—; Z is —O—,—C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—;

where

-   -   where R^(b) is —H; a —C₁₋₄alkyl group unsubstituted or        substituted with OH or halo; —CO₂C₁₋₄alkyl; or —CO₂H; and    -   R^(c) and R^(d) are each independently —H, —C₁₋₄alkyl,        —O—C₁₋₄alkyl, or halo;        -   or R^(c) and R^(d) taken together form an oxime, a C₁₋₄alkyl            oxime, or a carbonyl group;        -   or R^(c) and R^(d) taken together with the carbon to which            they are attached form a C₃₋₆cycloalkyl group;

R⁵ is:

i) a phenyl or phenoxy group, unsubstituted or substituted with one,two, or three R^(g) substituents;

-   -   where each R^(g) substituent is selected from the group        consisting of: —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂,        —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl,        —SO₂CF₃, —SCF₃, halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH,        monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and        oxadiazolyl;    -   or two R^(g) substituents taken together form —OCH₂O—, —OCF₂O—,        or —OCH₂CH₂O—;

ii) a naphthyl group, unsubstituted or substituted with C₁₋₄alkyl orhalo;

iii) a monocyclic heteroaryl group, unsubstituted or substituted withone, two, or three R^(g) substituents;

iv) a fused bicyclic heteroaryl group, unsubstituted or substituted withC₁₋₄alkyl or halo;

v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, andunsubstituted or substituted with one or two substituents selected fromthe group consisting of: —C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime,—C₁₋₄alkyl oxime, or phenyl; and

-   -   vi) a monocyclic heterocycloalkyl group, optionally fused to or        substituted with phenyl;

X is C or N; and

R⁶ or R⁷ are each independently —H, halo, —CF₃, thiophene, or—C(O)N(R^(x))R^(y);

wherein R^(x) and R^(y) are each independently —H or —C₁₋₄alkyl.

The invention also relates to stereoisomeric forms, hydrates, solvates,pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically active metabolites of compounds of Formula (I). Incertain preferred embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of an agentselected from compounds of Formula (I) and stereoisomeric forms,hydrates, solvates, pharmaceutically acceptable salts, pharmaceuticallyacceptable prodrugs, and pharmaceutically active metabolites thereof;and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition (collectively, “indications”) mediated by 5HT₇activity, comprising administering to the subject in need of suchtreatment an effective amount of a compound of Formula (I), or astereoisomeric form, hydrate, solvate, pharmaceutically acceptable salt,pharmaceutically acceptable prodrug, or pharmaceutically activemetabolite of such compound. In certain preferred embodiments of theinventive method, the disease, disorder, or medical condition isselected from: cognitive disorders, sleep disorders, psychiatricdisorders, and other disorders.

Preferred embodiments, features, and advantages of the invention will beapparent from the following detailed description and through practice ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED EMBODIMENTS

The invention may be more fully appreciated by reference to thefollowing detailed description, including the following glossary ofterms and the concluding examples. For the sake of brevity, thedisclosures of the publications, including patents, cited in thisspecification are herein incorporated by reference.

The terms “including”, “containing” and “comprising” are used herein intheir open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which may also be structurally depicted by a bond,“/”), ethyl (Et), n-propyl (Pr), isopropyl (iPr), butyl (nBu), isobutyl(iBu), sec-butyl (sBu), tert-butyl (tBu), pentyl, isopentyl,tert-pentyl, hexyl, isohexyl, and so on.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities (depicted without their bonds ofattachment):

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative examples (depictedwithout their bonds of attachment) include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities (depicted without their bonds of attachment):

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. It is understood that some compounds referred toherein are chiral and/or have geometric isomeric centers, for example E-and Z-isomers. All optical isomers and stereoisomers of the compounds ofany general structural formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any general formula given hereinis intended to represent a racemate, one or more enantiomeric forms, oneor more diastereomeric forms, one or more atropisomeric forms, andmixtures thereof. Furthermore, certain structures may exist as geometricisomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any general formula given herein is intended to embracehydrates, solvates, and polymorphs of such compounds, and mixturesthereof. Furthermore, certain compounds referred to herein can exist insolvated as well as unsolvated forms. It is understood that thisinvention encompasses all such solvated and unsolvated forms thatpossess the activity that characterizes the compounds of this invention.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any general formula given herein is also intended to represent unlabeledforms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures of the formulas givenherein except that one or more atoms are replaced by an atom having aselected atomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labeled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques(such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to a formula given herein, the selection of a particularmoiety from a list of possible species for a specified variable is notintended to define the moiety for the variable appearing elsewhere. Inother words, where a variable appears more than once in a formula, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula unlessotherwise indicated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g),R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as asR¹, R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and anyother generic substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n. Any disubstituent referred to herein is meantto encompass the various attachment possibilities when more than one ofsuch possibilities are allowed. For example, reference to disubstituent-A-B—, where A≠B, refers herein to such disubstituent with A attached toa first substituted member and B attached to a second substitutedmember, and it also refers to such disubstituent with A attached to thesecond substituted member and B attached to the first substitutedmember.

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as serotonin receptormodulators in the methods of the invention.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I), that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn, etal., “Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72,S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977,66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection,and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acidor glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I). A “pharmaceutically acceptableprodrug” is a prodrug that is non-toxic, biologically tolerable, andotherwise biologically suitable for administration to the subject.Illustrative procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Representative pharmaceutically acceptable amides ofthe invention include those derived from ammonia, primary C₁₋₆ alkylamines and secondary di(C₁₋₆alkyl) amines. Secondary amines include 5-or 6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceuticallyacceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl,phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methylesters. Prodrugs may also be prepared by derivatizing free hydroxygroups using groups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs. Carbonate derivatives, sulfonate esters,and sulfate esters of hydroxy groups may also provide prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group may be an alkyl ester, optionallysubstituted with one or more ether, amine, or carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, is also useful to yield prodrugs. Prodrugs of this typemay be prepared as described in Robinson et al., J Med Chem. 1996, 39(1), 10-18. Free amines can also be derivatized as amides, sulfonamidesor phosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I), which may also be used inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J Med Chem. 1997,40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of theseratonin receptor in the methods of the invention. As such modulators,the compounds may act as antagonists, agonists, or inverse agonists. Theterm “modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize or down-regulate seratonin receptor expression or activity,and “activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate seratonin receptor expression or activity.

Many of the compounds of the present invention are 5-HT₇ modulators thatact as 5-HT₇ antagonists. As such, the compounds are useful in thetreatment of 5-HT₇-mediated disease in which a decrease, prevention,inactivation, desensitization or down-regulation of serotonin receptorexpression or activity is required.

The term “treat” or “treating” as used herein is intended to refer toadministration of an active agent or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of serotonin receptor activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of serotonin receptor activity.The term “subject” refers to a mammalian patient in need of suchtreatment, such as a human.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician.

The invention may be particularly useful in the treatment or preventionof diseases, disorders, or conditions mediated by serotonin receptoractivity, such as: central nervous system disorders such as sleepdisorders (including insomnia), depression/anxiety, generalized anxietydisorder, schizophrenia, bipolar disorders, cognitive disorders, mildcognitive impairment, Alzheimer's disease, Parkinson's disease,psychotic disorders, phobic disorders, obsessive-compulsive disorder,mood disorders, post-traumatic stress and other stress-relateddisorders, migraine, pain, eating disorders, obesity, sexualdysfunction, metabolic disturbances, hormonal imbalance, hot flashesassociated with menopause, alcohol abuse, drug abuse, and addictivedisorders including drug addiction and alcohol addiction. Furtherdiseases associated with serotonin receptor activity for which thecompounds may be useful for treating are nausea, inflammation, centrallymediated hypertension, sleep/wake disturbances, jetlag, and circadianrhythm abnormalities. The compounds may also be used in the treatmentand prevention of hypotension, peripheral vascular disorders,cardiovascular shock, renal disorders, gastric motility, diarrhea,spastic colon, irritable bowel disorders, ischemias, septic shock,urinary incontinence and other disorders related to the gastrointestinaland vascular systems. In addition, compounds of the present inventionmay be used in methods for treating or preventing a range of oculardisorders including glaucoma, optic neuritis, diabetic retinopathy,retinal edema, and age-related macular degeneration. Symptoms or diseasestates are intended to be included within the scope of “medicalconditions, disorders, or diseases.”

The compounds of the present invention are 5-HT₇ modulators, many ofwhich are 5-HT₇ antagonists. As such, the compounds are useful in thetreatment of 5-HT₇ mediated disease states. Where the compounds possesssubstantial 5-HT₇ modulating activity, they may be particularly usefulin methods for treating depression/anxiety, sleep/wake disturbances,sleep disorders, jet lag, migraine, urinary incontinence, gastricmotility, and irritable bowel disorders, hypertension, analgesic, andirritable bowel syndrome.

Particularly, as serotonin receptor modulators, the compounds of thepresent invention are useful in the treatment or prevention ofdepression, anxiety, sleep disorders, and circadian rhythmabnormalities.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. In addition, the compounds of theinvention may be used in combination with additional active ingredientsin the treatment of the above conditions. In an exemplary embodiment,additional active ingredients are those that are known or discovered tobe effective in the treatment of conditions, disorders, or diseasesmediated by serotonin receptors or that are active against anothertarget associated with the particular condition, disorder, or disease.Suitable examples include: H₁ receptor antagonists, H₂ receptorantagonists, H₃ receptor antagonists, topiramate (TOPAMAX™), andneurotransmitter modulators such as norepinephrine reuptake inhibitors(NRIs), selective serotonin reuptake inhibitors (SSRls), noradrenergicreuptake inhibitors, non-selective serotonin re-uptake inhibitors(NSSRIs), acetylcholinesterase inhibitors (such astetrahydroaminoacridine, Donepezil (ARICEPT™), Rivastigmine, orGalantamine (REMINYL™)), modafinil, anti-psychotics, sedatives,monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants(TCAs). The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of a compound according to the invention), decrease one ormore side effects, or decrease the required dose of the compoundaccording to the invention. In preferred embodiments, the combinationmethod employs doses containing additional active ingredients in therange of about 20 to 300 mg per dose.

A pharmaceutical composition of the invention comprises: (a) aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof; and (b) a pharmaceuticallyacceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. It is anticipated that thecompounds of the invention can be administered by oral or parenteralroutes, including intravenous, intramuscular, intraperitoneal,subcutaneous, rectal and topical administration, and inhalation. Fororal administration, the compounds of the invention will generally beprovided in the form of tablets or capsules or as an aqueous solution orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate and lactose. Cornstarch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, will generally be magnesium stearate,stearic acid or talc. If desired, the tablets may be coated with amaterial such as glyceryl monostearate or glyceryl distearate, to delayabsorption in the gastrointestinal tract.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For intramuscular, intraperitoneal, subcutaneous and intravenoususe, the compounds of the invention will generally be provided insterile aqueous solutions or suspensions, buffered to an appropriate pHand isotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration andthe weight of the patient. In general, however, it is anticipated thatthe daily dose (whether administered as a single dose or as divideddoses) will be in the range 0.01 to 1000 mg per day, more usually from 1to 500 mg per day, and most usually from 10 to 200 mg per day. Expressedas dosage per unit body weight, a typical dose will be expected to bebetween 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedbelow. Pharmaceutically acceptable salts of the specific compoundsexemplified herein are especially preferred.

In certain embodiments of compounds of Formula (I), R¹ is —H,—C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl. In certainembodiments, R¹ is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,cyclopropyl, cyclobutyl, or benzyl. In further embodiments, R¹ is —H.

In certain embodiments of compounds of Formula (I), m has the value of1, 2 or 3 and n has the value of 1 or 2; however, if m is 2 then n isnot 1. In preferred embodiments, m is 1 and n is 1. In furtherembodiments, m is 1 and n is 2. In further embodiments, m is 2 and n is2. In further embodiments, m is 3 and n is 1.

In certain embodiments of compounds of Formula (I), R² is —H or—C₁₋₄alkyl. In further embodiments, R² is —H, or —CH₃.

In certain embodiments of compounds of Formula (I), R³ is —H or—C₁₋₄alkyl. In further embodiments, R³ is —H, or —CH₃.

In certain embodiments of compounds of Formula (I), R² and R³ are each—H.

In certain embodiments of compounds of Formula (I), R⁴ is —H, F,—C₁₋₄alkyl or R⁴ may be —OH when L is —CH₂—, —CF₂—, —CHF—, —OCH₂—, or—OCH(CH₃)—In further embodiments, R⁴ is hydrogen.

In certain embodiments of compounds of Formula (I), L is —O—, —CH₂—,—OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or —CHF—. In certain embodiments, Lis —O—.

In certain embodiments of compounds of Formula (I), Z is —O—, —C(O)—,—OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—; where R^(b) is —H; a —C₁₋₄alkylgroup unsubstituted or substituted with OH or halo; —CO₂C₁₋₄alkyl; or—CO₂H; and R^(c) and R^(d) are each independently —H, —C₁₋₄alkyl,—O—C₁₋₄alkyl, or halo. In certain embodiments of compounds of Formula(I), R^(c) and R^(d) taken together form an oxime, a C₁₋₄alkyl oxime, ora carbonyl group. In certain embodiments of compounds of Formula (I),R^(c) and R^(d) taken together with the carbon to which they areattached form a C₃₋₆cycloalkyl group. In certain embodiments ofcompounds of Formula (I), Z is —O—, —C(O)—, —OCH₂—, —OCH(CH₃)—,—OCH(CH₂CH₃)—, —OCH(CH₂OH)—, —OCH(CO₂H)—, —OCH(CH₂F)—, —OCH₂CH₂—,—OCH₂CH(F)—, —OCH₂CH(OCH₃)—, —OCH₂C(NOH)—, —OCH₂C(NOCH₃)—, —OCH₂CF₂—,—OCH₂C(O)—, or

In further embodiments, Z is —O—, —OCH₂—, or —OCH(CH₃)—.

In certain embodiments of compounds of Formula (I), R⁵ is a phenyl orphenoxy group, unsubstituted or substituted with one, two, or threeR^(g) substituents; where each R^(g) substituent is selected from thegroup consisting of —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂,—C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃,halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl,phenyl, thiophenyl, benzhydryl, and oxadiazolyl. In further embodimentsof compounds of Formula (I), two R^(g) substituents taken together form—OCH₂O—, —OCF₂O—, or —OCH₂CH₂O— group. In further embodiments, R⁵ is anaphthyl group, unsubstituted or substituted with C₁₋₄alkyl or halo. Infurther embodiments, R⁵ is a monocyclic heteroaryl group, unsubstitutedor substituted with one, two, or three R^(g) substituents. In furtherembodiments, R⁵ is a fused bicyclic heteroaryl group, unsubstituted orsubstituted with C₁₋₄alkyl or halo. In further embodiments, R⁵ is amonocyclic cycloalkyl group, optionally fused to a phenyl ring, andunsubstituted or substituted with one or two substituents selected fromthe group consisting of: —C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime,—C₁₋₄alkyl oxime, or phenyl. In further embodiments, R⁵ is a monocyclicheterocycloalkyl group, optionally fused to or substituted with phenyl.In further embodiments, R⁵ is cyclohexyl, 2-indanyl, or furanyloptionally substituted with one or more substituents individuallyselected from halo, —CH₃, —CF₃, —OCF₃, or —CN.

In certain embodiments, R⁵ is selected from the group consisting ofcyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl,phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl,3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl,3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3-or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl,3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl,3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl,4-fluoro-3-trifluoromethyl-phenyl, 3- or4-trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-phenyl,

3-azetidinyl, 1-benzyl-azetidin-3-yl, 1-benzhydryl-azetidin-3-yl,1-isopropyl-azetidin-3-yl, benzo[1,3]dioxol-5-yl,2,2-difluoro-benzo[1,3]dioxol-5-yl, 2-benzofuranyl, 5-benzofuranyl,2,3-dihydro-benzofuran-2-yl, 2-benzothiazolyl, 6-benzothiazolyl,1H-benzotriazole-6-yl, 1-methyl-1H-benzotriazole-6-yl, 2- or3-chromanyl, 2- or 3-furanyl, 5-trifluoromethyl-2-furanyl, 2-indanyl,tetrahydro-3-furanyl, 1-Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl,5-fluoro-1-indanyl, 5-methyl-1-indanyl, 5- or 6-chloro-1-indanyl,6-fluoro-1-indanyl, 6-trifluoromethyl-1-indanyl, 6-methyl-1-indanyl,5-fluoro-2-indanyl, 5-methoxy-2-indanyl, [1,2,4]oxadiazole-5-yl,3-cyclopropyl-[1,2,4]oxadiazole-5-yl,3-cyclobutyl-[1,2,4]oxadiazole-5-yl, 3-isopropyl-[1,2,4]oxadiazole-5-yl,phenoxy, 4-piperidinyl, 2- or 3-pyrrolidinyl,3-methyl-[1,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl,4-trifluoromethyl-2-pyridinyl, 2-, 3- or 4-pyridinyl,6-trifluoromethyl-2-pyridinyl, 1,2,3,4-tetrahydro-naphthalen-1-yl,1,2,3,4-tetrahydro-naphthalen-2-yl, 1-phenyl-3-azetidinyl, 4- or5-thiazolyl, 2-methyl-thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl,

and 5-methyl-isoxazole-3-yl.

In certain embodiments of compounds of Formula (I), R⁶ and R⁷ are eachindependently —H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y); whereinR^(x) and R^(y) are each independently —H or —C₁₋₄alkyl. In certainembodiments of compounds of Formula (I), R⁶ and R⁷ are eachindependently —H, halo, —CF₃, thiophene-3-yl, orN,N-dimethyl-formamidyl. In certain embodiments, R⁶ is —H or halo. Incertain embodiments, R⁶ is —H or halo and R⁷ is —H, halo, —CF₃,thiophene-3-yl, or N,N-dimethyl-formamidyl.

Preferred compounds are selected from the group consisting of:

EX. Chemical Name 1 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine; 23-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 33-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine; 43-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-propyl-azetidine; 53-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 63-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-ethyl-azetidine; 73-[5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 83-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 93-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonitrile; 103-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;113-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;12 3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine; 133-[5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy]-azetidine; 143-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidine; 153-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidine; 163-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine; 173-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidine; 183-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-ethyl-azetidine; 193-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-propyl-azetidine; 203-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 213-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine 223-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 233-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine; 243-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 253-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidine; 263-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine; 273-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine; 284-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole;29 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-thiazole; 303-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-methyl-isoxazole; 313-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-phenyl]-5-methyl-[1,2,4]oxadiazole; 323-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 333-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine; 343-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile; 353-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidine; 363-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidine; 373-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 383-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine; 393-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 403-(2-Benzyloxy-5-chloro-phenoxy)-azetidine; 413-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine;42 3-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 433-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 444-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile; 453-[2-(2,4-Bis-trifluoromethyl-benzyloxy)-5-chloro-phenoxy]-azetidine; 463-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine;473-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;483-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;493-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine;50 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine; 512-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 523-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 534-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 543-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;55 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylicacid ethyl ester; 563-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine;57 3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine; 58(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 59(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 60(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine; 61(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 624-(2-Benzyloxy-5-chloro-phenoxy)-piperidine; 634-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;644-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;65 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine; 664-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine; 674-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine; 684-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine; 69(±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;70 (±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine; 71(±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine; 723-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidine; 733-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidine; 743-(5-Bromo-2-cyclohexylmethoxy-phenoxy)-azetidine; 755-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid; 765-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester; 775-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl-furan-3-yl]-methanol; 783-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine; 792-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine;803-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoromethyl-pyridine; 812-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine;825-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-pyridine;83 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine; 846-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole; 856-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1-methyl-1H-benzotriazole;86 3-[5-Chloro-2-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethoxy)-phenoxy]-azetidine; 87 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-oxazole;88 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole; 893-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine; 90(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine; 91(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine; 92(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 93(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 94(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 95(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 96(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 97(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 98(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine; 99(±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester; 100 (±)-Methanesulfonic acid3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]- phenyl ester; 101(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;102(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;103(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine; 104(S)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 105(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;106(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-isopropyl-azetidine; 107(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-cyclobutyl-azetidine; 108(±)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 109(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine; 110(±)-3-[5-Bromo-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;111 (±)-3-[5-Bromo-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;112(±)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;113(R)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;114 (±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;115 (±)-3-[5-Chloro-2-[1-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;116 (±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;117(±)-3-[5-Chloro-2-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 118(±)-3-[5-Chloro-2-[1-(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 119(±)-3-[5-Chloro-2-[1-(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 120(±)-3-[5-Chloro-2-[1-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]-azetidine; 121(±)-3-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 122(±)-3-[5-Chloro-2-[1-(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine;123 (±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine;124 (±)-3-[5-Chloro-2-[1-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine;125(±)-3-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile;126(±)-3-[5-Chloro-2-[1-(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;127(±)-3-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine;128(±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine;129(±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine;130(±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine;131 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole;132 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole; 1332-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole; 1345-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole;135(R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;136 (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine;137(±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine;138 (±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine;139(R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine; 140(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine;141(±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine;142 3-[5-Bromo-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine; 1433-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine; 144(±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine; 145(±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine; 146(±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine;147 3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine; 1482-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol; 149[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid; 150(±)-3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine; 151(±)-3-[5-Bromo-2-(indan-1-yloxy)-phenoxy]-azetidine; 152(±)-3-[5-Bromo-2-(5-chloro-indan-1-yloxy)-phenoxy]-azetidine; 153(±)-3-[5-Bromo-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine; 154(±)-3-[5-Bromo-2-(5-fluoro-indan-1-yloxy)-phenoxy]-azetidine; 155(±)-3-[5-Bromo-2-(5-methyl-indan-1-yloxy)-phenoxy]-azetidine; 156(±)-3-[5-Bromo-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine; 157(±)-3-[5-Bromo-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine;158 (±)-3-[5-Chloro-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine; 159(±)-3-[5-Chloro-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine; 1603-[5-Chloro-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine; 1613-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-1-yloxy)-phenoxy]-azetidine;162 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine; 1633-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine; 1643-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine;165 3-[5-Chloro-2-(chroman-2-ylmethoxy)-phenoxy]-azetidine; 1663-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine; 1673-[5-Chloro-2-(chroman-3-ylmethoxy)-phenoxy]-azetidine; 1683-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine; 1693-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylmethoxy)-phenoxy]-azetidine;1705-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1,3-dimethyl-1H-pyrazole;171 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine; 1723-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-phenyl-azetidine; 1733-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine; 1743-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine; 1753-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine; 1763-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine; 1773-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine; 1783-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine; 1792-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime; 1802-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one O-methyl-oxime;181 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanone oxime;182 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanoneO-methyl- oxime; 1832-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-(4-chloro-phenyl)-ethanone;184 3-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine; 1853-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 1863-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 1873-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine; 1883-[5-Chloro-2-[1-(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;1893-[5-Chloro-2-[1-(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine;190 3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 1913-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 1923-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 1933-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 1943-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 1953-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine; 1963-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine; 1973-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine; 1983-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 1993-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 2003-[5-Trifluoromethyl-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 2013-[2-(1-Phenyl-ethoxy)-5-trifluoromethyl-phenoxy]-azetidine; 2023-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine; 2033-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-methyl-azetidine; 2043-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-isopropyl-azetidine; 2053-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-cyclobutyl-azetidine; 2063-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-propyl-azetidine; 2073-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-ethyl-azetidine; 2083-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;; 2093-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-1-isopropyl-azetidine; 2103-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine; 2113-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzamide; 2123-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine; 2133-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine; 2143-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine; 2153-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine; 2163-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine;217 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 2183-(5-Bromo-2-phenoxy-phenoxy)-3-methyl-azetidine; 219(±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine;220cis-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine;221 trans-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine; 2223-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine; 223(±)-3-[5-Chloro-2-(trans-1-benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine;224 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-azetidine; 2253-[5-Chloro-2-(1-benzhydryl-azetidin-3-ol)-phenoxy]-azetidine; 2263-[5-Chloro-2-(1-azetidin-3-ol)-phenoxy]-azetidine; 2273-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine;228 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine; 2293-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine; 2301-tert-Butyl-3-[5-chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine2311-tert-Butyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 2323-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine;233 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidine; 2343-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-1-methyl-azetidine; 2353-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol; 2363-[1-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol; 2373-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine; 2383-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine; 2395-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazole;240 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl-[1,2,4]oxadiazole; 2415-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl-[1,2,4]oxadiazole; 2425-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl-[1,2,4]oxadiazole; 2435-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1,2,4]oxadiazole;244 3-(5-Bromo-2-phenoxy-phenoxy)-azetidine; 2453-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy]-azetidine; 2463-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine; 2473-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine; 2483-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy]-azetidine; 2493-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine; 2503-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-azetidine; 2513-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine; 2523-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 2533-[5-Bromo-2-(3-trifluoromethoxy-phenoxy)-phenoxy]-azetidine; 2543-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine; 2553-[5-Bromo-2-(naphthalen-1-yloxy)-phenoxy]-azetidine; 2563-(5-Chloro-2-phenoxy-phenoxy)-azetidine; 2573-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 2583-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidine; 2593-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine; 2603-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine; 2612-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole; 2622-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole; 2632-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1,8]naphthyridine; 2642-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline; 2654-(5-Chloro-2-phenoxy-phenoxy)-piperidine; 266(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; 267(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; 268(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine; 269(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; 270(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; 271(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine; 272(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine; 273(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine; 274(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine; 275(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine; 276(S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine; 277(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine; 278(S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; 279(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; 2802-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone; 281[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone; 282[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone; 283[4-Bromo-2-(1-methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)-methanone; 284 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-methanone;285 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone; 286[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-methanone; 287[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone; 288[4-Bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl-methanone; 289[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1,3]dioxol-5-yl-methanone;290Benzo[1,3]dioxol-5-yl-[4-bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone; 291[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-methanone; 292[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone;293[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone;294 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone;295[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1,3]dioxol-5-yl-methanone;296Benzo[1,3]dioxol-5-yl-[4-chloro-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone; 297[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone; and298 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone;and stereoisomeric forms, hydrates, solvates, pharmaceuticallyacceptable salts, prodrugs, and active metabolites thereof.

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables in theformulas depicted in the schemes below are as defined above in referenceto Formula (I). Reactions may be performed between the melting point andthe reflux temperature of the solvent, and preferably between 0° C. andthe reflux temperature of the solvent.

List of abbreviations: Ac=Acetyl, AIBN=azobisisobutyronitrile,Boc=tert-Butylcarbamoyl, m-CPBA=meta-chloroperoxybenzoic acid,DCE=dichloroethane, DEAD=diethyldiazodicarboxylate, DIBAL-H=diisobutylaluminum hydride, DIEA=N,N-Diisopropylethylamine,DMA=N,N-Dimethylacetamide, DME=Ethylene glycol dimethyl ether,DMF=dimethylformamide, DMSO=Dimethyl sulfoxide, Et₃N=triethylamine,Et₂O=diethyl ether, EtOAc=Ethyl acetate, MeCN=acetonitrile,MeOH=methanol, MsCI=Methanesulfonyl chloride, TFA=trifluoroacetic acid,TFAA=trifluoroacetic acid anhydride, THF=tetrahydrofuran, TLC=thin layerchromatography,Q-Phos=1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.

The compounds of formula (I) may be prepared by a number of reactionschemes. The following schemes represent certain synthesis steps forobtaining compounds of the invention. Persons skilled in the art willrecognize that certain compounds are more advantageously produced by onescheme as compared to the other.

The amines in the compounds below may be protected, as indicated by P¹,as an alkyl or benzyl amine, amide, carbamate or other groups such asdescribed in “Protecting Groups in Organic Synthesis”, 3^(rd) ed.; T. W.Greene and P. G. Wuts, John Wiley and Sons, 1999. Preferably, P¹ is—C₁₋₆Alkyl, —COOC₁₋₆Alkyl, —(C═O)C₁₋₆Alkyl, benzyl substituted orunsubstituted with —OC₁₋₆Alkyl or C₁₋₆Alkyl, or benzhydryl substitutedor unsubstituted with —OC₁₋₆Alkyl or —C₁₋₆Alkyl). A further preferredprotecting group is t-butyl carbamate (Boc) or trifluoroacetamide. Thisprotecting group (P¹) on the nitrogen may be removed or converteddirectly into the desired compounds using generally accepted methodsknown to one skilled in the art. More specifically a group such as a Bocgroup may be removed with an acid such as trifluoroacetic acid orhydrochloric acid and the like in a solvent such as CH₂Cl₂, EtOAc, THF,1,4-dioxane, MeOH or EtOH. A group such as trifluoroacetamide wasremoved using a base such as NH₃, NH₄OH or K₂CO₃ in an alcoholic solventsuch as MeOH or EtOH and the like.

Intermediates of the formula A5 were prepared according to Scheme A. Thevariable Z in the formula depicted in Scheme 1 are as defined above inreference to Formula (I) except Z cannot be —C(O)— in Scheme 1.Compounds of the formula A1 were treated with tert-butylamine in thepresence of a dehydrating agent such as SiO₂, CuSO₄, Ti(OiPr)₄, MgSO₄ ormolecular sieves in a suitable solvent such as THF, CH₂Cl₂, benzene,toluene, MeOH or EtOH. A preferred method uses MgSO₄ in CH₂Cl₂ to givecompounds of the formula A2. Compounds of the formula A2 were allowed toreact with compounds of the formula A3 in a suitable solvent such asDMF, DMSO, NMP or THF in the presence of a base such as NaH, KOtBu orCs₂CO₃, preferably NaH in DMF, to produce compounds of formula A4.Compounds of the formula A5 were obtained from compounds of the formulaA4 upon basic hydrolysis of the compound obtained from the treatment ofcompounds of the formula A4 with an oxidant such asm-chloroperoxybenzoic acid (m-CPBA) in CH₂Cl₂. The hydrolysis isperformed using a base such as NaOH or KOH in a solvent such as MeOH,EtOH or H₂O.

Intermediates of the formula A4 were alternatively prepared according toScheme B. Compounds of the formula A4 were alternatively obtained fromcompounds of the formula B1, where LG represents a chloride, bromide,iodide, mesylate or tosylate, upon treatment with a compound of theformula B2. The variable Z in the formulas depicted in Scheme 2 are asdefined above in reference to Formula (I) except Z cannot be —C(O)— inScheme 2. This type of reaction was carried out in a solvent such asDMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃,K₂CO₃ or Cs₂CO₃. Alternatively, compounds of the formula A4 may also beobtained from compounds of the formula B1 when LG is OH using PPh₃ orsimilar trialkyl or triaryl phosphine and diethyldiazodicarboxylate(DEAD), diisopropyldiazodicarboxylate (DIAD) ordi-tert-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF,THF or CH₂Cl₂ and the like. One skilled in the art will recognize thisas a Mitsunobu reaction.

Intermediates of the formula C3 were prepared according to Scheme C.Compounds of the formula C3 were synthesized similar to compounds of theformula A5 (Scheme 1) from compounds of the formula C1. Compounds of theformula C2 were obtained from compounds of the formula C1 and compoundsof the formula A2 (Scheme 1) in a suitable solvent such as DMF, DMSO,NMP or THF in the presence of a base such as NaH, KOtBu or Cs₂CO₃,preferably NaH in DMF. Compounds of the formula C3 were obtained fromcompounds of the formula C2 upon basic hydrolysis of the compoundobtained from the treatment of compounds of the formula C2 with anoxidant such as m-chloroperoxybenzoic acid (m-CPBA) in CH₂Cl₂. Thehydrolysis was performed using a base such as NaOH or KOH in a solventsuch as MeOH, EtOH or H₂O.

Intermediates of the formula C2 were alternatively prepared according toScheme D using compounds of the formula D1. The amine in compounds ofthe formula C2 may be protected with a protecting group, as indicated byP¹, with previously described protecting groups. Treatment of compoundsof formula D1 with a nucleophile such as a compound of formula B2(Scheme 2) in the presence of base such as pyridine, triethylamine,diisopropylamine, K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such asTHF, CH₂Cl₂, DMF, MeCN, 1,4-dioxane or the like at a temperature rangingfrom rt to 100° C. provided compounds of the formula C2. Compounds ofthe formula D1 were obtained from compounds of the formula C1 whentreated with methanesulfonyl chloride (MsCl) in the presence of a basesuch as pyridine, triethylamine or diisopropylamine and the like in asolvent such as CH₂Cl₂, THF or DCE.

Intermediates of the formula E2 were prepared according to Scheme E.Compounds of the formula E2 were obtained after addition of compounds ofthe formula E2 to compounds of the formula E1. One skilled in the artwill recognize compounds of the formula E2 as Grignard reagents.

Intermediates of the formula F4 were prepared according to Scheme F.Compounds of the formula F4 were prepared from compounds of the formulaF2, where LG represents a Cl or Br, and F3. Compounds of the formula F2were prepared from compounds of the formula F1 upon treatment with anoxidizing agent such as m-CPBA in a solvent such as CH₂Cl₂.

Intermediates of the formula G7 were prepared according to Scheme G.Compounds of the formula G3 were synthesized from compounds of theformula G1 and compounds of the formula G2 using solvents such as Et₂O,THF, CH₂Cl₂, or dioxane and the like. One skilled in the art willrecognize G1 as a Weinreb amide (Nahm, S. et al., Tet. Lett., 1981, 22,3815-3818) and G2 as a Grignard reagent. Compounds of the formula G4were obtained from compounds of the formula G3 by partial reduction withhydride donors such as NaBH₄ in alcoholic solvents such as MeOH, EtOH ori-PrOH and the like followed by further reduction using H₂ in thepresence of a hydrogenation catalyst such as Pd/C, PtO₂ or Pd(OH)₂ andthe like at pressures up to 60 psi and temperatures ranging from rt to60° C. in solvents such as MeOH, EtOH or i-PrOH and the like. The Bocprotecting group in compounds of the formula G2 was exchanged for atrifluoroacetamide as shown in compounds of the formula G5 by treatmentwith acids such as trifluoroacetic acid or hydrochloric acid and thelike in a solvent such as CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOH or EtOH.Treatment of the intermediate from this reaction with trifluoroaceticanhydride (TFAA) in the presence of a base such as pyridine,triethylamine or diisopropylethylamine or the like in a solvent such asCH₂Cl₂, THF, DMF, MeOH, EtOH or the like yields compounds of the formulaG5. Treatment of compounds of the formula G5 with an electrophilicbromine source such as Br₂, NBS, NaBr/oxone or chlorine source such asCl₂, KCl/oxone or NCS and the like in a solvent such as MeOH, CH₂Cl₂,EtOH, DMF, acetone, H₂O and the like or mixtures there of producescompounds of the formula G6. Treatment of compounds of the formula G6with a reagent such as Lil in collidine, HBr in AcOH, or preferrablyBBr₃ in CH₂Cl₂, produces compounds of the formula G7.

Intermediates of the formula H6 were prepared according to Scheme H.Compounds of the formula H3 were obtained from compounds of the formulaC3 upon treatment with compounds of the formula H1, representing analkyl chloride, bromide, iodide, mesylate or tosylate in a solvent suchas DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃,Na₂CO₃, K₂CO₃ or Cs₂CO₃. Alternatively, compounds of the formula H3 mayalso be obtained from compounds of the formula H2 when X is OH usingPPh₃ or similar trialkyl or triaryl phosphine anddiethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD)or di-tert-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN,DMF, THF or CH₂Cl₂ and the like. One skilled in the art will recognizethis as a Mitsunobu reaction. The transformation when X is OH may alsobe performed using cyanomethylene-tri-n-butylphosphine in a solvent suchas PhCH₃ when heated in a microwave reactor at temperatures up to 120°C. When R₅ is a substituted aryl or heteroaryl, compounds of the formulaH3 were obtained using Cu(OAc)₂ and base such as pyridine or Et₃N andthe like in the presence of dehydrating agents such as MgSO₄ or 4 Åmolecular sieves.

Compounds such as H6 were prepared from compounds of the formula H4using methods such as reductive amination or alkylation. Thus treatmentof H4 with a compound of formula H5 containing a carbonyl in thepresence of a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogengas in the presence of a catalyst in a solvent such as CH₂Cl₂, THF, DCE,MeOH, EtOH or similar afforded compounds of the formula H6. One skilledin the art will recognize that the presence of Bronsted or Lewis acidsmay be required. Examples of acids may include AcOH, Ti(O-iPr)₄,trifluoroacetic acid or hydrochloric acid and the like. One skilled inthe art will also recognize that compounds of the formula H6 may beobtained from H4 upon treatment with an alkyl chloride, bromide, iodide,mesylate or tosylate and the like in a solvent such as DMF, DMA, THF orEtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.It will be generally recognized that compounds of the formula H6represent a subset of compounds of the formula H4 where R₁ is equal toH. Compounds of the formula H4 or H6 may be converted to theircorresponding salts using methods generally accepted to those skilled inthe art.

Intermediates of the formula H1 were prepared according to Scheme I whennot commercially available.

Intermediates of the formula J4 were prepared according to Scheme J.Compounds of the formula J4 were prepared from compounds of the formulaJ1 and compounds of the formula J3 (prepared as in Scheme A) usingcyanomethylene-tri-n-butylphosphine in a solvent such as PhCH₃ whenheated in a microwave reactor at temperatures up to 120° C. In thisreaction scheme, the preferred protecting group, P¹ is a benzhydrylgroup. Alternatively, compounds of the formula J4 were also synthesizedfrom compounds of the formula D1 (Scheme D). Treatment of a compound offormula D1 with a nucleophile such as a compound of formula J3 in thepresence of base such as pyridine, triethylamine, diisopropylamine,K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF,MeCN, 1,4-dioxane or the like at a temperature ranging from rt to 100°C. provided compounds of the formula J4.

Intermediates of the formula K4 were prepared according to Scheme K. Thevariable R^(n) in the formulas depicted in Scheme K are —H or—C₁₋₄alkyl. The variable Z in the formulas depicted in Scheme K are asdefined above in reference to Formula (I) except Z cannot be —C(O)— inScheme K. Compounds of the formula K2 were obtained from compounds ofthe formula K1 and compounds of the formula A4 in the presence ofcyanomethylene-tri-n-butylphosphine in a solvent such as PhCH₃ whenheated in a microwave reactor at temperatures up to 120° C.Alternatively, when the protecting group on nitrogen was a benzhydryl asin compounds of the formula K3 compounds of the formula K4 were obtainedusing similar conditions.

Intermediates of the formula L4 were prepared according to Scheme L. Thevariable Z in the formulas depicted in Scheme L are as defined above inreference to Formula (I) except Z cannot be —C(O)— in Scheme L. Theamine in compounds of the formula L3 may be protected, as indicated byP¹, as discussed previously. Compounds of the formula L3 were preparedfrom compounds of the formula L2 and compounds of the formula C1 in thepresence of base such as pyridine, triethylamine, diisopropylamine,K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF,MeCN, 1,4-dioxane or the like at a temperature ranging from rt to 100°C. Compounds of the formula L2 were prepared from compounds of theformula L1 by treatment with a chlorinating agent such as SOCl₂ in asolvent such as CH₂Cl₂. Compounds of the formula L1 were prepared fromcompounds of the formula A4 using a reducing agent such as NaBH₄, LiBH₄,Dibal-H, LiAlH₄ and the like in a solvent such as CH₂Cl₂, THF, DCE, MeOHor EtOH and the like.

Intermediates of the formula M5 were prepared according to Scheme M. Thevariable Z in the formulas depicted in Scheme M are as defined above inreference to Formula (I) except Z cannot be —C(O)— in Scheme M.Compounds of the formula M4 may be prepared from compounds of theformula M3 and compounds of the formula C1 using a base such as NaH andthe like in a solvent such as THF, DMF, NMP or DMSO at temperatures upto 145° C. in a microwave reactor. Compounds of the formula M3 may beprepared from compounds of the formula M1 and compounds of the formulaM2 using a base such as NaH and the like in a solvent such as THF, DMF,NMP or DMSO and the like.

Compounds of the formula M5 may be obtained from compounds of theformula M4 by removal of the P¹ group. The amine in compounds of theformula M4 may be protected, as indicated by P¹, as describedpreviously. A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. It will be generally recognized that compounds ofthe formula M5 may be converted to their corresponding salts usingmethods generally accepted to those skilled in the art.

Intermediates of the formula N5 were prepared according to Scheme N.Compounds of the formula N5 may be obtained from compounds of theformula N4 by removal of the P¹ group. The amine in compounds of theformula N4 may be protected, as indicated by P¹, as describedpreviously. A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. It will be generally recognized that compounds ofthe formula N5 may be converted to their corresponding salts usingmethods generally accepted to those skilled in the art.

Compounds of the formula N4 were prepared from compounds of the formulaN2 and compounds of the formula N3 in the presence of a base such asdiisopropyethylamine, Et₃N or pyridine and the like upon heating in amicrowave reactor at temperatures up to 145° C. Precursors to compoundsof the formula N2 were prepared from compounds of the formula N1 andbromomethyl acetate in a solvent such as DMF, DMA, THF or EtOH in thepresence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Subsequenthydrolysis using aqueous NaOH followed by formation of compounds of theformula N2 using oxalyl chloride in a solvent such as THF, CH₂Cl₂ orPhCH₃ in the presence of a catalytic amount of DMF provided compounds ofthe formula N2.

Intermediates of the formula O6 were prepared according to Scheme O. Theamine in compounds of the formula O5 may be protected, as indicated byP¹ as described previously. A preferred protecting group is t-butylcarbamate (Boc) or trifluoroacetamide. Compounds of the formula O6 wereobtained from compounds of the formula O5 by removal of the P¹ group. Itwill be generally recognized that compounds of the formula O6 may beconverted to their corresponding salts using methods generally acceptedto those skilled in the art.

Compounds of the formula O5 were prepared form compounds of the formulaO3 and compounds of the formula O4 using a base such as NaHCO₃, Na₂CO₃,K₂CO₃ or Cs₂CO₃ in solvents such as MeOH, EtOH or iPrOH. Compounds ofthe formula O3 were prepared from compounds of the formula C3 andcompounds of the formula O2 by heating the mixture up to 100° C. in amicrowave reactor in a solvent such as DMF, DMA, THF or EtOH in thepresence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Compounds ofthe formula O2 were obtained by bromination of compounds of the formulaO1 using (Bu)N₄Br₃ (TBABr₃) in a solvent mixture of MeOH and CH₂Cl₂.

Intermediates of the formula P1 were prepared according to Scheme P.Compounds of the formula P1 were synthesized from compounds of theformula O3 using a hydride donor such as Et₃SiH in the presence of anacid such as trifluoroacetic acid in a solvent such as DCE or CH₂Cl₂.

Intermediates of the formula Q5 were prepared according to Scheme Q.Compounds of the formula Q3 were prepared from compounds of the formulaQ2 by oxidation with an oxidant such as the Dess-Martin periodinane in asolvent such as CH₂Cl₂. Compounds of the formula Q2 were prepared fromcompounds of the formula C2 (Scheme C) and compounds of the formula Q1in solvents such as Et₂O, THF, CH₂Cl₂, or dioxane and the like.

Compounds of the formula Q4 may be obtained from compounds of theformula Q3 by removal of the P¹ group. The amine in compounds of theformula Q3 may be protected, as indicated by P¹ as described previously.A preferred protecting group is t-butyl carbamate (Boc) ortrifluoroacetamide. It will be generally recognized that compounds ofthe formula Q4 represent a subset of compounds of the formula Q5 whereR₆ is equal to H. Compounds of the formula Q4 or Q5 may be converted totheir corresponding salts using methods generally accepted to thoseskilled in the art.

Compounds such as Q5 were prepared from compounds of the formula Q4using methods such as reductive amination or alkylation. Thus treatmentof Q4 with a compound containing a carbonyl in the presence of areductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in thepresence of a catalyst in a solvent such as CH₂Cl₂, THF, DCE, MeOH, EtOHor similar afforded compounds of the formula Q5. One skilled in the artwill recognize that the presence of Bronsted or Lewis acids may berequired. Examples of acids may include AcOH, Ti(O-iPr)₄,trifluoroacetic acid or hydrochloric acid and the like. One skilled inthe art will also recognize that compounds of the formula Q5 may beobtained from Q4 upon treatment with an alkyl chloride, bromide, iodide,mesylate or tosylate and the like in a solvent such as DMF, DMA, THF orEtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Intermediates of the formula R3 were prepared according to Scheme R.Compounds of the formula R2 were synthesized from compounds of theformula R1 (prepared as outlined in Scheme G) using an oxidant such asm-CPBA in a solvent such as CH₂Cl₂. Compounds of the formula R3 may beobtained from compounds of the formula R2 by removal of the P¹ group.The amine in compounds of the formula R2 may be protected, as indicatedby P¹ as described previously. A preferred protecting group is t-butylcarbamate (Boc) or trifluoroacetamide.

Intermediates of the formula S4 were prepared according to Scheme S.Compounds of the formula S2 were obtained from compounds of the formulaS1 by bromination using NBS in the presence of AIBN in solvents such asCCl₄ at refluxing temperatures. Compounds of the formula S3 wereobtained from compounds of the formula N1 and compounds of the formulaS2 in a solvent such as DMF, DMA, THF or EtOH in the presence of basessuch as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ followed by a work-up withneutral H₂O. A preferred protecting group on compounds of the formula N1was Boc.

Intermediates of the formula T2 were prepared according to Scheme T.Compounds of the formula T1 were obtained from compounds of the formulaN1 and compounds of the formula S2 in a solvent such as DMF, DMA, THF orEtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃followed by a work-up with basic H₂O where the pH was >10. A preferredprotecting group on compounds of the formula N1 was Boc.

Intermediates of the formula U2 were prepared according to Scheme U.Compounds of the formula U2 were prepared from compounds of the formulaU1 using reducing agents such as Dibal-H in solvents such as CH₂Cl₂, THFor PhCH₃ and the like.

Intermediates of the formula V3 were prepared according to Scheme V.Compounds of the formula V2 were prepared from compounds of the formulaV1 using reducing agents such as LiBH₄ and the like in solvents such asCH₂Cl₂, THF or PhCH₃ and the like. Compounds of the formula V3 wereprepared from compounds of the formula V2 using acids such astrifluoroacetic acid or hydrochloric acid and the like in a solvent suchas CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOH or EtOH.

Intermediates of the formula W2 were prepared according to Scheme W.Compounds of the formula W1 were prepared from compounds of the formulaV1 by hydrolysis using aqueous hydroxide bases such as NaOH or KOH andthe like with an organic co-solvent such as THF or MeOH. A preferredprotecting group on compounds of the formula V1 was Boc.

Intermediates of the formula X4 were prepared according to Scheme X. Apreferred protecting group on compounds of the formula X1 was Boc.Compounds of the formula X3, were prepared from compounds of the formulaX1 and compounds of the formula X2 by heating in a microwave reactor attemperatures up to 170° C. in the presence of Hermann's catalyst,Mo(CO)₆ and bases such as Na₂CO₃ and the like.

Intermediates of the formula Y3 were prepared according to Scheme Y. Apreferred protecting group on compounds of the formula X1 was Boc.Compounds of the formula Y2, were prepared from compounds of the formulaX1 by treatment with compounds of the formula Y1 in the presence of acatalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂,PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF,DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃,CsF, KF, K₃PO₄, KOAc or the like and a ligand typically used in suchreactions such as Q-Phos, dppf, dppe or PPh₃ and the like attemperatures ranging from rt to 160° C. using conventional or microwaveheating.

EXAMPLES Chemistry

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions were “dried,” they were generallydried over a drying agent such as Na₂SO₄ or MgSO₄ then filtered andconcentrated. Where mixtures, solutions, and extracts were“concentrated”, they were typically concentrated on a rotary evaporatorunder reduced pressure.

Thin-layer chromatography (TLC) was performed using Merck silica gel 60F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography (PTLC) was performed usingEM Science silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates witha 20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) eluting with 2 M NH₃ in MeOH/CH₂Cl₂ or EtOAc in hexanes,unless otherwise noted.

Preparative reversed-phase HPLC (RP HPLC) was performed on a HewlettPackard HPLC Series 1100, with a Phenomenex Luna C18 (5 μm, 4.6×150 mm)column. Detection was done at 2=230, 254 and 280 nm. The gradient was 10to 99% acetonitrile/H₂O (0.05% trifluoroacetic acid) over 5.0 min with aflow rate of 1 mL/min. Alternatively, HPLC was performed on a DionexAPS2000 LC/MS with a Phenomenex Gemini C18 (5 μm, 30×100 mm) column, anda gradient of 5 to 100% acetonitrile/H₂O (20 mM NH₄OH) over 16.3 min,and a flow rate of 30 mL/min. Preparative RP HPLC was also performed onan Agilent 1100 preparative system with a Waters X-Bridge C18 (5 μm,30×100 mm) column, and a gradient of 5 to 99% acetonitrile/H₂O (20 mMNH₄OH) over 17 min, and a flow rate of 80 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference or relative toresidual protic solvent (multiplicity, coupling constant J in Hz,integration).

Chemical names were generated using ChemDraw Version 6.0.2(CambridgeSoft, Cambridge, Mass.).

General Procedures

General Procedure 1 (Removal of Boc Qroups):

Boc groups were deprotected using TFA/CH₂Cl₂ (1:1) or 4M HCl indioxane/EtOAc (1:1). The compounds were then either neutralized andextracted with CH₂Cl₂ or characterized as the hydrochloride ortrifluoroacetate salt where indicated.

General Procedure 2 (Removal of Trifluroacetamide Groups):

Trifluoroacetamide groups were deprotected using K₂CO₃ (1 eq.) in MeOH(0.2 M), 2M NH₃ in MeOH or 5N NH₄OH (aq.) in MeOH. After 15 h, H₂O wasadded and the mixture extracted with EtOAc (2×). The combined organicswere dried and concentrated. Purification using silica gelchromatoraphy, reverse-phase HPLC or PTLC then provided the deprotectedamines.

General Procedure 3 (Reductive Amination):

To amine in CH₂Cl₂ (0.1 M) was added ketone (1.2-5.0 eq.) and NaBH(OAc)₃(1.2 eq.). After 18 h, the reaction was typically treated with 5% Na₂CO₃(aq.) and extracted with CH₂Cl₂ (2×). The combined organics were driedand purified using silica gel chromatography, reverse-phase HPLC orPTLC.

General Procedure 4 (Reductive Amination):

To amine in MeOH (0.1 M) was added ketone or aldehyde (1.2-5.0 eq.),AcOH (10 mol %) and NaCNBH₃ (1.2 eq.). After 18 h, the reaction wastypically treated with 5% Na₂CO₃ (aq.) and extracted with CH₂Cl₂ (2×).The combined organics were dried and purified using silica gelchromatography, reverse-phase HPLC or PTLC.

General Procedure 5 (NH to NMe):

To amine in MeOH (0.1 M) was added excess 37 wt % [H₂CO]n in H₂O andNaBHOAc₃ (1.2 eq.). After 18 h, 5% Na₂CO₃ (aq.) was added and themixture extracted with CH₂Cl₂. The combined organics were dried andpurified using silica gel chromatography, reverse-phase HPLC or PTLC toyield the corresponding methylated analogs.

General Procedure 6 (Cu(OAc)2-Mediated Diaryl Ether Synthesis):

To a phenol in DCE (0.1 M) was added arylboronic acid (2 eq.), Cu(OAc)₂(1 eq.), MgSO₄ (2 eq) or 4 Å molecular sieves and Et₃N (5 eq). Thereactions were allowed to stir open to the air for 12-48 h, thenfiltered, concentrated and purified using silica gel chromatography,reverse-phase HPLC or PTLC.

General Procedure 7 (Mitsunobu Reaction):

To phenol (1 eq), alcohol (1 eq) and either PPh₃ (1.2 eq) or resin-boundPPh₃ in THF (0.2 M) at 0° C. or rt was added DEAD (1.1 eq) dropwise.After judged complete, the reactions were concentrated and purifiedusing silica gel chromatography, reverse phase HPLC or PTLC.

Example 1 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine

Step A: Preparation of (4-bromo-2-fluoro-benzylidene)-tert-butyl-amine

To a CH₂Cl₂ (900 mL) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g,246 mmol) was added tert-butylamine (42.3 mL, 29.3 g, 400 mmol) andMgSO₄ (60.0 g, 499 mmol). After 48 h, the solution was filtered andconcentrated to give 62.0 g (98%) of the title compound as a yellowliquid. ¹H NMR (CDCl₃): 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.32-7.25(m, 2H), 1.29 (s, 9H).

Step B: Preparation of3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To a 0° C. DMF (720 mL) solution of the title compound of Step A (37.2g, 144 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester(25.0 g, 144 mmol) was added NaH (60 wt % in mineral oil, 7.50 g, 188mmol) portionwise over 2 h. The reaction was then allowed to warm to rt.After 18 h, H₂O was added and the reaction mixture was extracted withEtOAc (2×). The combined organic layers were washed with brine andconcentrated to give a yellow liquid that was treated with THF (360 mL),H₂O (360 mL) and AcOH (25 mL). After 5 h, this solution was made basicwith 5% Na₂CO₃ (aq.) and extracted with EtOAc (2×). The combined organiclayers were washed with brine and dried. The resulting solid was thentriturated with 20% EtOAc in hexanes to give 41.9 g (82%) of the titlecompound as a white solid. ¹H NMR (CDCl₃): 10.43 (s, 1H), 7.74 (d, J=8.3Hz, 1H), 7.26-7.23 (m, 1H), 6.77 (d, J=1.6 Hz, 1H), 5.01-4.95 (m, 1H),4.39 (ddd, J=9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J=6.4, 0.8 Hz, 2H), 1.46(s, 9H).

Step C: Preparation of3-(5-Bromo-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To a CH₂Cl₂ (280 mL) solution of the title compound of Step B (24.7 g,69.4 mmol) was added 77% m-CPBA (23.3 g, 104 mmol). After 15 h, 10%Na₂S20₅ (aq.) was added and the solution allowed to stir until theaqueous was KI paper negative then extracted with CH₂Cl₂ (2×). Thecombined organic layers were washed with saturated NaHCO₃ (aq.),concentrated and treated with MeOH (220 mL) and 1 N NaOH (220 mL). After15 h, the reaction was partially concentrated to remove the MeOH,acidified with 1M KHSO₄ (220 mL) and extracted with CH₂Cl₂ (2×). Thecombined organic layers were washed with brine and dried providing abrown solid that was triturated with EtOAc/hexanes giving 17.6 g (74%)of the title compound as a white solid. ¹H NMR (CDCl₃): 7.03 (dd, J=8.5,2.1 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.93-4.89(m, 1H), 4.34 (dd, J=10.1, 6.8 Hz, 1H), 4.03 (dd, J=9.9, 3.7 Hz, 1H),1.46 (s, 9H).

Step D: Preparation of3-(2-benzyloxy-5-bromo-phenoxy)-azetidine-1-carboxylic acid tert-butylester

To a DMF (10 mL) solution of the title compound of Step C (0.52 g, 1.5mmol), Cs₂CO₃ (0.54 g, 1.7 mmol) and KI (0.20 g, 1.20 mmol) was addedbenzyl bromide (0.20 mL, 0.29 g, 1.7 mmol). After 48 h, H₂O was addedand the mixture extracted with EtOAc (2×). The combined organics werewashed with brine (2×) and dried. Silica gel chromatography (5-20% EtOAcin hexanes) gave 0.65 g (99%) of the title compound as a clear oil. ¹HNMR (CDCl₃): 7.42-7.36 (m, 3H), 7.34-7.31 (m, 2H), 7.03 (dd, J=8.6, 2.3Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.09 (s, 2H),4.88-4.83 (m, 1H), 4.26 (ddd, J=9.7, 6.5, 0.9 Hz, 2H), 4.05 (dd, J=9.8,4.0 Hz, 2H), 1.45 (s, 9H).

Step E: Preparation of 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine

Synthesized according to general procedure 1 from the title compound ofStep D. MS (ESI): mass calcd. for C₁₆H₁₆BrNO₂, 333.0; m/z found, 334.0[M+H]⁺. ¹H NMR (CDCl₃): 7.08 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz,1H), 6.67 (d, J=2.2 Hz, 1H), 4.86 (tt, J=6.5, 4.3 Hz, 1H), 4.29 (ddd,J=9.7, 6.5, 0.8 Hz, 2H), 4.08 (dd, J=10.1, 4.2 Hz, 2H), 3.85 (s, 3H),1.44 (s, 9H).

Unless otherwise specified the compounds in Examples 2-74 were preparedsimilar to Example 1 using the appropriately substituted phenol andalkyl halide.

Example 2 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺.¹H NMR (CDCl₃): 7.47-7.43 (m, 1H), 7.31-7.27 (m, 3H), 7.00 (dd, J=8.6,2.3 Hz, 1H), 6.78-6.73 (m, 2H), 5.06 (s, 2H), 5.01-4.95 (m, 1H),3.94-3.83 (m, 4H).

The compounds in Examples 3-6 were prepared from the title compound ofExample 2 using general procedure 3 or 4.

Example 33-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁BrClNO₂, 422.7; m/z found, 423.9 [M+H]⁺.¹H NMR (CDCl₃): 7.43 (s, 1H), 7.32-7.26 (m, 3H), 6.98 (dd, J=8.5, 2.3Hz, 1H), 6.75 (dd, J=13.6, 5.4 Hz, 2H), 5.05 (s, 2H), 4.77-4.72 (m, 1H),3.78-3.65 (m, 2H), 3.12-3.16 (m, 3H), 2.01-1.95 (m, 2H), 1.87-1.79 (m,2H), 1.78-1.69 (m, 2H).

Example 4 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-propyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found, 411.9 [M+H]⁺.¹H NMR (CDCl₃): 7.44 (s, 1H), 7.33-7.27 (m, 3H), 7.02-6.95 (m, 1H), 6.76(dd, J=13.4, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.74 (m, 1H), 3.88-3.80 (m,2H), 3.14-3.06 (m, 2H), 2.52-2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t,J=7.4 Hz, 3H).

Example 53-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found, 411.9 [M+H]⁺.¹H NMR (CDCl₃): 7.44 (s, 1H), 7.32-7.27 (m, 3H), 6.99 (dd, J=8.6, 2.3Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.98 (s, 2H),4.75-4.70 (m, 1H), 3.88-3.71 (m, 2H), 3.15-2.94 (m, 2H), 2.43-2.38 (m,1H), 0.99-0.95 (m, 6H).

Example 6 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-ethyl-azetidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 396.7; m/z found, 397.0 [M+H]⁺.¹H NMR (CDCl₃): 7.44 (d, J=1.8, 1H), 7.35-7.26 (m, 3H), 6.99 (dd, J=8.6,2.3 Hz, 1H), 6.76 (dd, J=14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.73 (m,1H), 3.873.79 (m, 2H), 3.11-3.08 (m, 2H), 2.55 (q, J=7.2, 2H), 1.00 (t,J=7.2 Hz, 3H).

Example 7 3-[5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅BrF₃NO₃, 417.0; m/z found, 418.1 [M+H]⁺.¹H NMR (CDCl₃): 7.40 (t, J=8.1 Hz, 1H), 7.34-7.33 (m, 2H), 7.18-7.16 (m,1H), 7.00 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.73 (d,J=2.3 Hz, 1H), 5.10 (s, 2H), 5.01-4.96 (m, 1H), 3.93-3.86 (m, 4H).

Example 8 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅BrF₃NO₂, 401.0; m/z found, 401.9 [M+H]⁺.¹H NMR (CDCl₃): 7.75 (s, 1H), 7.60 (t, J=7.2 Hz, 2H), 7.51 (t, J=7.7 Hz,1H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.74 (d,J=2.3 Hz, 1H), 5.14 (s, 2H), 5.01-4.95 (m, 1H), 3.93-3.86 (m, 4H).

Example 9 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonitrile

¹H NMR (CDCl₃): 7.78 (s, 1H), 7.67-7.61 (m, 2H), 7.50 (t, J=7.7 Hz, 1H),7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz,1H), 5.12 (s, 2H), 5.02-4.96 (m, 1H), 3.95-3.86 (m, 4H).

Example 103-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrF₃NO₃, 391.0; m/z found, 392.1 [M+H]⁺.¹H NMR (CDCl₃): 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H),6.79-6.76 (m, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.47 (d, J=3.3 Hz, 1H), 5.06(s, 2H), 5.00-4.93 (m, 1H), 3.96-3.89 (m, 2H), 3.88-3.79 (m, 2H).

Example 113-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄BrClF₃NO₃, 451.0; m/z found, 452.0[M+H]⁺. ¹H NMR (CDCl₃): 7.62-7.59 (m, 2H), 7.35-7.32 (m, 2H), 7.02 (dd,J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 5.06(s, 2H), 5.03-4.96 (m, 1H), 3.98-3.91 (m, 2H), 3.89-3.83 (m, 2H).

Example 12 3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄BrClFNO₂, 385.0; m/z found, 386.1[M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=7.0, 2.1 Hz, 1H), 7.31-7.25 (m, 1H),7.15 (dd, J=8.7, 8.6 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d,J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 5.03 (s, 2H), 5.01-4.95 (m, 1H),3.99-3.91 (m, 2H), 3.90-3.81 (m, 2H).

Example 133-[5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₃, 397.0; m/z found, 398.1 [M+H]⁺.¹H NMR (CDCl₃): 7.48 (d, J=2.1 Hz, 1H), 7.29-7.25 (m, 1H), 7.02 (dd,J=8.6, 2.3 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.73(d, J=2.3 Hz, 1H), 5.01 (s, 2H), 5.00-4.94 (m, 1H), 3.96-3.83 (m, 4H),3.92 (s, 3H).

Example 14 3-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.00; m/z found, 368.1[M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.30 (m, 4H), 7.12 (dd, J=8.7, 2.3 Hz, 1H),6.87 (d, J=2.3 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 5.06-4.99 (m, 3H),4.31-4.13 (m, 4H).

Example 15 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (dd, J=5.5, 3.8 Hz, 1H), 7.41 (dd, J=5.6, 3.7 Hz,1H), 7.32-7.27 (m, 2H), 7.13 (dd, J=8.7, 2.2 Hz, 1H), 6.89 (d, J=2.3 Hz,1H), 6.83 (d, J=8.7 Hz, 1H), 5.14 (s, 2H), 5.07-4.99 (m, 1H), 4.26-4.21(m, 4H).

Example 16 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 15 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/z found,382.1 [M+H]⁺. ¹H NMR (CDC₃): 7.59-7.51 (m, 1H), 7.39 (dd, J=7.4, 1.7 Hz,1H), 7.32-7.23 (m, 2H), 7.00 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (dd, J=5.4,3.1 Hz, 2H), 5.19 (s, 2H), 4.78-4.73 (m, 1H), 3.92-3.78 (m, 2H),3.21-3.11 (m, 2H), 2.42 (s, 3H).

Example 17 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidinetrifluroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrFNO₂, 351.0; m/z found, 352.1 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (dt, J=7.9, 5.9 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H),7.13-7.08 (m, 2H), 7.03 (dt, J=8.4, 2.1 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H),6.80 (d, J=8.7 Hz, 1H), 5.04 (s, 3H), 4.29-4.22 (m, 4H).

The compounds in Examples 18-21 were prepared from the title compound ofExample 17 using general procedure 3 or 4.

Example 18 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-ethyl-azetidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 380.3; m/z found, 381.1 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.31 (m, 1H), 7.17-7.15 (m, 2H), 7.00-6.97 (m, 2H),6.76 (dd, J=16.1, 5.4 Hz, 2H), 5.08 (s, 2H), 4.78-4.74 (m, 1H),3.85-3.82 (m, 2H), 3.13-3.05 (m, 2H), 2.57-2.53 (m, 2H), 1.00 (t, J=7.2Hz, 3H).

Example 19 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-propyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrFNO₂, 394.3; m/z found, 395.1 [M+H]⁺.¹H NMR (CDCl₃): 7.34-7.21 (m, 1H), 7.15-7.13 (m, 2H), 7.02-6.92 (m, 2H),6.74 (dd, J=14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.76-4.72 (m, 1H),3.85-3.77 (m, 2H), 3.11-3.04 (m, 2H), 2.46 (dd, J=8.8, 6.0 Hz, 2H),1.43-1.32 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

Example 203-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrFNO₂, 394.3; m/z found, 395.1 [M+H]⁺.¹H NMR (CDCl₃): 7.34-7.30 (m, 1H), 7.18-7.12 (m, 2H), 7.02-6.94 (m, 2H),6.80-6.71 (m, 2H), 5.07 (s, 2H), 4.74-4.69 (m, 1H), 3.85-3.78 (m, 2H),3.12-3.06 (m, 2H), 2.43-2.36 (m, 1H), 0.96 (d, J=6.2 Hz, 6H).

Example 213-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁BrFNO₂, 406.3; m/z found, 407.1 [M+H]⁺.¹H NMR (CDCl₃): 7.34-7.30 (m, 1H), 7.19-7.09 (m, 2H), 7.04-6.87 (m, 2H),6.75 (dd, J=14.4, 5.4 Hz, 2H), 5.07 (s, 2H), 4.77-4.72 (m, 1H),3.82-3.57 (m, 2H), 3.28-2.99 (m, 3H), 2.03-1.92 (m, 2H), 1.88-1.78 (m,2H), 1.77-1.70 (m, 2H).

Example 22 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 368.7; m/z found, 369.1 [M+H]⁺.¹H NMR (CDCl₃): 7.47 (s, 1H), 7.33-7.29 (m, 3H), 7.06-6.99 (m, 2H), 6.50(d, J=8.4 Hz, 1H), 5.07 (s, 2H), 5.00-4.93 (m, 1H), 3.94-3.82 (m, 4H).

Example 233-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

Synthesized from the title compound of Example 22 according to generalprocedure 3. MS (ESI): mass calcd. for C₂₀H₂₁BrClNO₂, 422.7; m/z found,423.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.46-7.41 (m, 1H), 7.35-7.25 (m, 3H),7.03-6.95 (m, 2H), 6.53 (d, J=8.6 Hz, 1H), 5.03 (s, 2H), 4.76-4.70 (m,1H), 3.73-3.65 (m, 2H), 3.22-3.10 (m, 3H), 2.02-1.90 (m, 2H), 1.88-1.57(m, 4H).

Example 243-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

Synthesized from the title compound of Example 22 according to generalprocedure 3. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found,412.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.34-7.22 (m, 3H), 7.04-6.99(m, 2H), 6.59-6.53 (m, 1H), 5.04 (s, 2H), 4.74-4.68 (m, 1H), 3.83-3.76(m, 2H), 3.11-3.04 (m, 2H), 2.43-2.34 (m, 1H), 0.99-0.90 (m, 6H).

Example 25 3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidinehydrochloride

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺.¹H NMR (DMSO-D₆): 9.37 (s, 2H), 7.51 (dd, J=8.7, 5.6 Hz, 2H), 7.23 (t,J=8.9 Hz, 2H), 7.1 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.4 Hz, 1H), 6.92(d, J=2.4 Hz, 1H), 5.11 (s, 2H), 5.08-5.02 (m, 1H), 4.37 (dd, J=12.5,6.7 Hz, 2H), 3.98 (dd, J=12.5, 5.0 Hz, 2H).

Example 26 3-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNo₂S, 335.1; m/z found, 336.1 [M+H]⁺.¹H NMR (CDCl₃): 7.33-7.29 (m, 2H), 7.18 (dd, J=13.3, 7.8 Hz, 2H),6.86-6.81 (m, 2H), 6.59 (d, J=2.1 Hz, 1H), 5.07 (s, 2H), 5.01-4.95 (m,1H), 3.94-3.84 (m, 4H), 2.49 (2, 3H).

Example 273-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

Step A: Preparation of3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Example 26 (0.050 g, 0.10 mmol) in CH₂Cl₂ (1mL) was added 77% m-CPBA (0.06 g, 0.25 mmol). After 18 h, 10% Na₂S₂O₅(aq.) was added and the mixture extracted with CH₂Cl₂ (2×). The combinedorganics were dried. Silica gel chromatography gave 0.038 g (80%) of thetitle compound as a clear oil. MS (ESI): mass calcd. for C₂₂H₂₆ClNO₆S,467.1; m/z found, 368.1 [M−100]⁺, 490.1 [M+Na]⁺. ¹H NMR (CDCl₃): 8.03(s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.57 (d,J=2.3 Hz, 1H), 5.17 (s, 2H), 4.91-4.85 (m, 1H), 4.31 (dd, J=10.4, 6.4Hz, 2H), 4.08-4.03 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H).

Step B: Preparation of3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

Prepared from the title compound of Step A using general procedure 1. MS(ESI): mass calcd. for C₁₇H₁₈ClNO₄S, 367.1; m/z found, 368.0 [M+H]⁺. ¹HNMR (CDCl₃): 8.10 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.7 Hz,1H), 7.60 (t, J=7.8 Hz, 1H), 6.89-6.83 (m, 2H), 6.60 (d, J=2.1 Hz, 1H),5.17 (s, 2H), 5.03-4.97 (m, 1H), 3.97-3.85 (m, 4H), 3.07 (s, 3H).

Example 284-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S₂, 378.0; m/z found, 379.1[M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=3.7, 0.9 Hz, 1H), 7.40 (dd, J=5.0,0.9 Hz, 1H), 7.25 (m, 1H), 7.08 (dd, J=5.0, 3.7 Hz, 1H), 6.92-6.86 (m,2H), 6.60 (d, J=2.3 Hz, 1H), 5.25 (s, 2H), 5.01-4.97 (m, 1H), 3.95-3.85(m, 4H).

Example 294-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-thiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S, 310.1; m/z found, 311.2 [M+H]⁺.¹H NMR (CDCl₃): 7.15 (d, J=10.2 Hz, 1H), 6.95-6.85 (m, 2H), 6.59 (d,J=2.1 Hz, 1H), 5.18 (d, J=0.8 Hz, 2H), 5.00-4.95 (m, 1H), 3.93-3.87 (m,4H), 2.73 (s, 3H).

Example 303-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-methyl-isoxazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₃, 294.1; m/z found, 295.2 [M+H]⁺.¹H NMR (CDCl₃): 6.90 (d, J=8.6 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H),6.58 (d, J=2.3 Hz, 1H), 6.13 (s, 1H), 5.14 (s, 2H), 4.99-4.94 (m, 1H),3.96-3.89 (m, 2H), 3.87-3.80 (m, 2H), 2.43 (s, 3H).

Example 313-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxvmethyl]-phenyl]-5-methyl-[1,2,4]oxadiazolehydrochloride

MS (ESI): mass calcd. for C₁₉H₁₈ClN₃O₃, 371.1; m/z found, 372.2 [M+H]⁺.¹H NMR (DMSO-D₆): 9.22 (s, 2H), 8.10 (s, 1H), 7.95 (d, J=7.7 Hz, 1H),7.65 (d, J=7.7 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H),7.03 (dd, J=8.7, 2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 5.24 (s, 2H),5.09-5.05 (m, 1H), 4.41 (dd, J=12.5, 6.7 Hz, 2H), 4.02 (dd, J=12.3, 4.9Hz, 2H), 2.67 (s, 3H).

Example 323-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.0 [M+H]⁺.¹H NMR (CDCl₃): 7.79 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.57 (t,J=7.6, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.80(d, J=8.6 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.30 (s, 2H), 5.03-4.97 (m,1H), 3.96-3.85 (m, 4H).

Example 33 3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found, 320.2 [M+H]⁺.¹H NMR (CDCl₃): 7.31-7.22 (m, 1H), 7.00-6.95 (m, 2H), 6.86-6.78 (m, 3H),6.58 (d, J=2.1 Hz, 1H), 5.07 (s, 2H), 4.99-4.94 (m, 1H), 3.94-3.82 (m,4H), 3.80 (s, 3H).

Example 34 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂, 314.1; m/z found, 315.1 [M+H]⁺.¹H NMR (CDCl₃): 7.78 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.7 Hz,1H), 7.49 (t, J=7.8 Hz, 1H), 6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d,J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.11 (s, 2H), 5.04-4.99 (m, 1H),3.98-3.91 (m, 2H), 3.89-3.81 (m, 2H).

Example 35 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidinetrifluroacetate

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (dd, J=5.5, 3.8 Hz, 1H), 7.43-7.39 (m, 1H),7.32-7.27 (m, 2H), 6.98 (dd, J=8.7, 2.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H),6.75 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 5.07-4.99 (m, 1H), 4.34-4.19 (m,4H).

Example 36 3-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺.¹H NMR (CDCl₃): 7.35 (q, J=8.6 Hz, 4H), 6.95 (dd, J=8.7, 2.4 Hz, 1H),6.83 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 5.08-4.95 (m, 3H),4.31-4.24 (m, 4H).

Example 37 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺.¹H NMR (CDCl₃): 7.45 (s, 1H), 7.32-7.27 (m, 3H), 6.85 (td, J=8.5, 1.9Hz, 1H), 6.81 (dd, J=8.6, 4.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.06 (d,J=3.9 Hz, 2H), 5.00-4.95 (m, 1H), 3.95-3.84 (m, 4H).

Example 383-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 37 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found,338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.32-7.27 (m, 3H), 6.84 (dd,J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 5.06(s, 2H), 4.74-4.69 (m, 1H), 3.88-3.82 (m, 2H), 3.21-3.11 (m, 2H), 2.42(s, 3H).

Example 393-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.1 [M+H]⁺.¹H NMR (CDCl₃): 7.74 (s, 1H), 7.59 (t, J=8.6 Hz, 2H), 7.50 (t, J=7.7 Hz,1H), 6.87 (dd, J=8.6, 2.2 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.60 (d,J=1.7 Hz, 1H), 5.13 (s, 2H), 5.01-4.96 (m, 1H), 3.96-3.85 (m, 4H).

Example 40 3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₆ClNO₂, 289.1; m/z found, 290.1 [M+H]⁺.¹H NMR (CDCl₃): 7.39 (d, J=4.4 Hz, 4H), 7.36-7.31 (m, 1H), 6.96 (dd,J=8.7, 2.4 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.03(s, 2H), 5.01-4.95 (m, 1H), 4.39-4.15 (m, 4H).

Example 413-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄Cl₂F₃NO₃, 407.0; m/z found, 408.0[M+H]⁺. ¹H NMR (CD₃OD/CDC₃): 7.61-7.59 (m, 1H), 7.38-7.30 (m, 2H), 6.87(dd, J=8.6, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H),5.06 (s, 2H), 5.03-4.93 (m, 1H), 4.25-3.60 (m, 4H).

Example 423-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₃, 373.1; m/z found, 374.0 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.86(dd, J=8.6, 2.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H),5.09 (s, 2H), 5.02-4.94 (m, 1H), 4.00-3.80 (m, 4H).

Example 433-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.1 [M+H]⁺.¹H NMR (CDCl₃): 7.64 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 6.85(dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H),5.15 (s, 2H), 5.02-4.94 (m, 1H), 4.01-3.79 (m, 4H).

Example 44 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂, 314.1; m/z found, 315.0 [M+H]⁺.¹H NMR (CDCl₃): 7.68 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 6.86(dd, J=8.6, 2.4 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H),5.15, (s, 2H), 5.04-4.94 (m, 1H), 4.02-3.79 (m, 4H).

Example 453-[2-(2,4-Bis-trifluoromethyl-benzyloxy)-5-chloro-phenoxy]-azetidine

¹H NMR (CDCl₃, CD₃OD): 8.04-7.92 (m, 2H), 7.01 (dd, J=8.7, 2.3 Hz, 1H),6.94 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 5.36, (s, 2H), 5.20-2.11(m, 1H), 4.49 (dd, J=12.4, 6.7 Hz, 2H), 4.22 (dd, J=12.4, 5.2 Hz, 2H).

Example 463-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂S, 389.1; m/z found, 390.1[M+H]⁺. ¹H NMR (CDCl₃): 7.67 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H),6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz,1H), 5.13 (s, 2H), 5.05-4.93 (m, 1H), 4.04-3.78 (m, 4H).

Example 473-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄ClF₄NO₂, 375.1; m/z found, 377.0 [M+H]⁺.¹H NMR (CDCl₃): 7.77-7.70 (m, 1H), 7.64-7.57 (m, 1H), 7.25-7.18 (m, 1H),6.88 (dd, J=8.6, 2.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.3 Hz,1H), 5.08 (s, 2H), 5.02-4.94 (m, 1H), 3.98-3.90 (m, 2H), 3.87-3.80 (m,2H).

Example 483-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

¹H NMR (CDCl₃): 7.70 (dd, J=7.6, 7.4 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),7.35 (d, J=9.8 Hz, 1H), 6.88-6.84 (m, 2H), 6.61 (d, J=2.0 Hz, 1H), 5.20(s, 2H), 5.02-4.94 (m, 1H), 3.97-3.90 (m, 2H), 3.88-3.81 (m, 2H).

Example 493-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄C₁₂F₃NO₂, 391.0; m/z found, 392.0[M+H]⁺. ¹H NMR (CDCl₃): 7.73 (d, J=6.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.21(dd, J=9.4, 9.2 Hz, 1H), 6.90-6.81 (m, 2H), 6.59 (d, J=1.6 Hz, 1H),5.10-5.05 (m, 1H), 5.08, (s, 2H), 5.05-4.95 (m, 4H).

Example 50 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄C₁₃NO₂, 357.0; m/z found, 359.9 [M+H]⁺.¹H NMR (CDCl₃): 7.56 (d, J=1.8 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.24(dd, J=8.3, 1.9 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.04, (s, 2H), 5.05-5.00 (m, 1H),4.52-3.00 (m, 4H).

Example 51 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺.¹H NMR (CDCl₃): 8.62-8.57 (m, 1H), 7.75-7.69 (m, 1H), 7.55 (d, J=7.8 Hz,1H), 7.25-7.20 (m, 1H), 6.85-6.82 (m, 2H), 6.60 (d, J=1.6 Hz, 1H), 5.24(s, 2H), 5.09-4.94 (m, 1H), 4.18-3.64 (m, 4H).

Example 52 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺.¹H NMR (CD₃OD/CDC₃): 8.68-8.61 (m, 1H), 8.53 (d, J=4.3 Hz, 1H), 7.86 (d,J=7.9 Hz, 1H), 7.45-7.37 (m, 1H), 6.93-6.87 (m, 2H), 6.63-6.60 (m, 1H),5.13 (s, 2H), 5.04-4.94 (m, 1H), 4.12-3.70 (m, 4H).

Example 53 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺.¹H NMR (CD₃OD/CDC₃): 8.56-8.53 (m, 2H), 7.50-7.44 (m, 2H), 6.92-6.86 (m,2H), 6.66 (d, J=2.1 Hz, 1H), 5.18 (s, 2H), 5.09-5.01 (m, 1H), 4.04-3.94(m, 2H), 3.88-3.80 (m, 2H).

Example 543-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃ClF₃NO₃, 347.1; m/z found, 348.2 [M+H]⁺.¹H NMR (CDCl₃): 6.90-6.88 (m, 2H), 6.77-6.76 (m, 1H), 6.60 (s, 1H),6.46-6.45 (m, 1H), 5.05 (s, 2H), 4.98-4.93 (m, 1H), 3.94-3.90 (m, 2H),3.85-3.82 (m, 2H).

Example 555-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylic acidethyl ester

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₅, 351.1; m/z found, 352.2 [M+H]⁺.¹H NMR (CDCl₃): 7.13 (d, J=3.4 Hz, 1H), 6.89-6.85 (m, 2H), 6.58 (d,J=1.6 Hz, 1H), 6.50 (d, J=3.4 Hz, 1H), 5.08 (s, 2H), 4.98-4.93 (m, 1H),4.37 (q, J=7.1 Hz, 1H), 3.94-3.90 (m, 2H), 3.86-3.83 (m, 2H), 1.38 (t,J=7.1 Hz, 1H).

Example 563-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

¹H NMR (CD₃OD/CDCl₃): 7.65 (s, 1H), 7.33-7.27 (m, 2H), 6.64 (d, J=8.7Hz, 1H), 6.58 (dd, J=8.7, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 5.03 (s,2H), 4.71-4.63 (m, 1H), 3.99 (dd, J=12.6, 6.6 Hz, 2H), 3.70 (dd, J=12.5,5.1 Hz, 2H), 2.84 (s, 3H).

Example 57 3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₂NO₂, 325.1; m/z found, 327.1 [M+H]⁺.¹H NMR (CDCl₃): 7.52-7.43 (m, 1H), 6.92-6.80 (m, 4H), 6.60-6.58 (m, 1H),5.10 (s, 2H), 5.00-4.93 (m, 1H), 4.11-3.69 (m, 4H).

Example 58 (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇C₁₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺.¹H NMR (CDCl₃): 7.43 (s, 1H), 7.30-7.25 (m, 3H), 6.87-6.81 (m, 3H), 5.02(s, 2H), 4.83-4.81 (m, 1H), 3.23-3.17 (m, 2H), 2.99 (dd, J=12.8, 4.7 Hz,1H), 2.91 (ddd, J=11.3, 8.5, 5.5 Hz, 1H), 2.11-2.00 (m, 2H).

Example 59(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 58 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₈H₁₉Cl₂NO₂, 351.1; m/z found,352.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.29-7.28 (m, 3H), 6.85-6.79(m, 3H), 5.04 (s, 2H), 4.83-4.80 (m, 1H), 2.96 (dd, J=10.6, 6.1 Hz, 1H),2.80-2.75 (m, 2H), 2.58-2.54 (m, 1H), 2.41 (s, 3H), 2.32-2.36 (m, 1H),2.08-2.02 (m, 1H).

Example 60 (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇C₁₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺.¹H NMR (CDCl₃): 7.56-7.54 (m, 1H), 7.39-7.37 (m, 1H), 7.30-7.24 (m, 2H),6.88-6.86 (m, 3H) 5.15 (s, 2H), 4.84-4.82 (m, 1H), 3.23-3.16 (m, 2H),2.98 (dd, J=12.8, 4.6 Hz, 1H), 2.90 (ddd, J=11.3, 8.5, 5.5 Hz, 1H),2.12-2.00 (m, 2H).

Example 61(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 60 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₈H₁₉C₁₂NO₂, 351.1; m/z found,352.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.60-7.58 (m, 1H), 7.38-7.37 (m, 1H),7.29-7.23 (m, 2H), 6.85-6.82 (m, 3H) 5.17 (s, 2H), 4.85-4.81 (m, 1H),2.95 (dd, J=10.6, 6.1 Hz, 1H), 2.78-2.73 (m, 2H), 2.57-2.53 (m, 1H),2.39 (s, 3H), 2.32-2.36 (m, 1H), 2.08-2.02 (m, 1H).

Example 62 4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.3 [M+H]⁺.¹H NMR (CDCl₃): 7.42-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.29 (m, 1H),6.93-6.93 (m, 1H), 6.87-6.82 (m, 2H), 5.08 (s, 2H), 4.35-4.29 (m, 1H),3.17-3.11 (m, 2H), 2.68 (ddd, J=12.6, 9.3, 3.1 Hz, 2H), 2.02-1.96 (m,2H), 1.74-1.66 (m, 2H).

Example 634-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidinehydrochloride

MS (ESI): mass calcd. for C₁₇H₁₇ClF₃NO₃, 375.1; m/z found, 378.2. ¹H NMR(DMSO-D₆): 9.10-9.00 (m, 2H), 7.24-7.23 (m, 2H), 7.15 (d, J=8.7 Hz, 1H),7.01 (d, J=8.7, 2.5 Hz, 1H), 6.80 (d, J=3.2 Hz, 1H), 5.17 (s, 2H),4.59-4.55 (m, 1H), 3.20-3.17 (m, 2H), 3.03-3.00 (m, 2H), 2.07-2.02 (m,2H), 1.86-1.82 (m, 2H).

Example 644-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₇H₁₇BrF₃NO₃, 419.0; m/z found, 420.1 [M+H]⁺.¹H NMR (CDCl₃): 7.09 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.5, 2.3 Hz, 1H),6.84 (d, J=8.6 Hz, 1H), 6.79-6.75 (m, 1H), 6.45 (d, J=3.3 Hz, 1H), 5.06(s, 2H), 4.37-4.29 (m, 1H), 3.21-3.10 (m, 2H), 2.78-2.66 (m, 2H),2.06-1.95 (m, 2H), 1.76-1.66 (m, 2H).

Example 65 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1 [M+H]⁺.¹H NMR (CDCl₃): 7.45 (s, 1H), 7.29-7.27 (m, 3H), 7.07 (d, J=7.1 Hz, 1H),7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.04 (s, 2H),4.36-4.30 (m, 1H), 3.18-3.12 (m, 2H), 2.73-2.67 (m, 2H), 2.02-1.97 (m,2H), 1.75-1.67 (m, 2H).

Example 664-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine

Synthesized from the title compound of Example 65 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 409.0; m/z found,410.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (s, 1H), 7.30-7.28 (m, 3H), 7.06 (d,J=2.3 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H),5.04 (s, 2H), 4.32-4.29 (m, 1), 2.73-2.67 (m, 2H), 2.35-2.27 (m, 4H),2.02-1.85 (m, 4H).

Example 67 4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.2 [M+H]⁺.¹H NMR (CDCl₃): 7.52-7.49 (m, 1H), 7.33-7.28 (m, 1H), 7.15 (t, J=7.5 Hz,1H), 7.09-7.05 (m, 2H), 7.03-7.01 (m, 1H), 6.83 (dd, J=8.6, 2.4 Hz, 1H),5.12 (s, 2H), 4.34-4.29 (m, 1H), 3.15-3.13 (m, 2H), 2.71-2.62 (m, 2H),2.00-1.94 (m, 2H), 1.72-1.66 (m, 2H).

Example 68 4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.2 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.31 (m, 1H), 7.18-7.15 (m, 2H), 7.07 (d, J=2.3 Hz,1H), 7.02-6.98 (m, 2H), 6.78 (d, J=8.6 Hz, 1H), 5.07 (s, 2H), 4.36-4.31(m, 1H), 3.17-3.14 (m, 2H), 2.71 (t, J=9.6 Hz, 2H), 2.03-2.00 (m, 2H),1.75-1.67 (m, 2H).

Example 69(±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₇H₁₇ClF₃NO₃, 375.1; m/z found, 376.0 [M+H]⁺.¹H NMR (CDCl₃): 6.96-6.95 (m, 1H), 6.88-6.87 (m, 2H), 6.76-6.75 (m, 1H),6.45-6.44 (m, 1H), 5.04 (s, 2H), 4.22-4.17 (m, 1H), 3.12 (dd, J=2.2,12.7 Hz, 1H), 2.88-2.82 (m, 2H), 2.78-2.72 (m, 1H), 2.02-1.96 (m, 1H),1.85-1.74 (m, 2H), 1.53-1.45 (m, 1H).

Example 70 (±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.12; m/z found, 318.1 [M+H]⁺.¹H NMR (CDCl₃): 7.45-7.28 (m, 5H), 6.95 (d, J=2.1 Hz, 1H), 6.90-6.81 (m,2H), 5.08 (s, 2H), 4.20 (dq, J=10.2, 3.3 Hz, 1H), 3.11 (dd, J=12.7, 2.3Hz, 1H), 2.91-2.78 (m, 2H), 2.78-2.69 (m, 1H), 2.05-1.94 (m, 1H),1.88-1.74 (m, 2H), 1.53-1.41 (m, 1H).

Example 71(±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.11; m/z found, 386.0[M+H]⁺. ¹H NMR (CDCl₃): 7.75 (s, 1H), 7.62-7.56 (m, 2H), 7.50 (t, J=7.7Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d,J=8.6 Hz, 1H), 5.12 (s, 2H), 4.28-4.16 (m, 1H), 3.13 (dd, J=12.6, 2.3Hz, 1H), 2.91-2.80 (m, 2H), 2.78-2.67 (m, 1H), 2.08-1.94 (m, 1H),1.88-1.73 (m, 2H), 1.55-1.40 (m, 1H).

Example 72 3-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₄H₁₈ClNO₂, 267.1; m/z found, 268.2 [M+H]⁺.¹H NMR (CDCl₃): 6.97 (dd, J=8.7, 2.5 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H),6.75 (d, J=2.5 Hz, 1H), 5.04-4.99 (m, 1H), 4.76-4.67 (m, 1H), 4.38-4.27(m, 4H), 1.96-1.87 (m, 2H), 1.84-1.74 (m, 4H), 1.69-1.59 (m, 2H).

Example 73 3-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₆H₂₂ClNO₂, 295.1; m/z found, 296.2 [M+H]⁺.¹H NMR (CDCl₃): 6.97 (dd, J=8.7, 2.3 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H),6.74 (d, J=2.4 Hz, 1H), 5.15-4.97 (m, 1H), 4.44-4.36 (m, 2H), 4.30 (s,2H), 3.74 (d, J=6.3 Hz, 2H), 1.89-1.65 (m, 6H), 1.36-1.14 (m, 3H), 1.03(m, 2H).

Example 74 3-(5-Bromo-2-cyclohexylmethoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₂₂BrNO₂, 339.1; m/z found, 340.1 [M+H]⁺.¹H NMR (CDCl₃): 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H),6.71 (d, J=2.3 Hz, 1H), 4.97-4.92 (m, 1H), 3.92-3.83 (m, 4H), 3.75 (d,J=6.4 Hz, 2H), 1.95-1.63 (m, 6H), 1.36-1.14 (m, 3H), 1.10-0.93 (m, 2H).

Example 755-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylicacid trifluoroacetate

Step A: Preparation of5-Bromomethyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester

To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acidethyl ester (0.95 g, 4.5 mmol) in CCl₄ (12 mL) was addedN-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01mmol). After refluxing for 2 h, analytical HPLC analysis confirmed thereaction was complete. The reaction was cooled to rt, then CH₂Cl₂ andsat'd NaHCO₃ (aq.) were added. The organic portion was separated anddried to provide the crude residue as a yellow oil. This material waspurified by RP HPLC to provide the title compound (510 mg, 38%). MS(ESI): mass calcd. for C₉H₈BrF₃O₃, 300.0; m/z found, 302.9 [M+H]⁺. ¹HNMR (CDCl₃): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36(t, J=7.1 Hz, 3H).

Step B: Preparation of3-[2-(4-Carboxy-5-trifluoromethyl-furan-2-ylmethoxy)-5-chloro-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

The title compound was prepared as described in Example 1 Step D using3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (0.15 g, 0.50 mmol), the title compound of Step A (0.18 g, 0.60mmol), Cs₂CO₃ (0.41 g, 1.2 mmol), KI (0.12 g, 0.70 mmol) in DMF, exceptupon completion of the reaction 1N NaOH and EtOAc were added. Theorganic layer was washed with 1N NaOH and dried. The crude material waspurified by RP HPLC to provide the title compound. ¹H NMR (CDCl₃):7.20-6.92 (m, 1H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1Hz, 1H), 4.87 (s, 2H), 4.79-4.69 (m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88(m, 2H), 1.38 (s, 9H).

Step C: Preparation of5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylicacid trifluoroacetate

Prepared from the title compound of Step B using general procedure 1. MS(ESI): mass calcd. for C₁₆H₁₃ClF₃NO₅ [M-TFA], 391.0; m/z found, 392.9[M+H]⁺. ¹H NMR (CD₃OD): 7.10 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.4 Hz,1H), 6.99 (s, 1H), 6.88 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 5.11-5.04 (m,1H), 4.49 (dd, J=12.4, 6.6 Hz, 2H), 4.22 (dd, J=12.4, 4.9 Hz, 2H).

Example 765-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylicacid ethyl ester

Step A: Preparation of3-[5-Chloro-2-(4-ethoxycarbonyl-5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

The title compound was prepared as described in Example 1 Step D using3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (0.3 g, 1.0 mmol), the title compound of Example 75 Step A (0.75g, 2.5 mmol), Cs₂CO₃ (0.80 g, 2.4 mmol) and KI (0.23 g, 1.4 mmol) in DMF(15 mL). The crude material was purified by RP HPLC to provide the titlecompound (0.37 g, 71%). ¹H NMR (CDCl₃): 7.20-6.92 (m, 1H), 6.91-6.80 (m,2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.87 (s, 2H), 4.79-4.69(m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).

Step B: Preparation of5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylicacid ethyl ester: Prepared from the title compound of Step A usinggeneral procedure 1. MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₅, 419.1; m/zfound, 420.0 [M+H]⁺. ¹H NMR (CDCl₃): 6.94-7.80 (m, 3H), 6.65-6.56 (m,1H), 5.05 (s, 2H), 5.01-4.92 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.97-3.81(m, 4H), 1.36 (t, J=7.1 Hz, 3H).

Example 775-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl-furan-3-yl]-methanol

Step A: Preparation of5-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxvmethyl]-2-trifluoromethyl-furan-3-yl]-methanol

To a solution of the title compound of Example 76 Step A (0.05 g, 0.1mmol) at −78° C. was added DIBAL-H (1.0 M in THF, 0.24 mL). Afteraddition was complete, the bath was replaced with a 0° C. bath andallowed to stir for 1 h. Then, an additional aliquot of DIBAL-H (1.0 Min THF, 1 mL) was added. After 3 h, the reaction was quenched with asaturated solution of sodium potassium tartrate (aq.) and allowed tostir overnight. The mixture was extracted with EtOAc (2×) and thecombined organic layers were dried. The product was purified by RP HPLCto provide the title compound (0.004 g, 10%). MS (ESI): mass calcd. forC₁₇H₁₇ClF₃NO₄, 391.1; m/z found, 392.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.94 (d,J=8.6 Hz, 1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.65 (s, 1H), 6.54 (d,J=2.3 Hz, 1H), 5.02 (s, 2H), 4.73-4.66 (m, 1H), 4.64 (d, J=1.4 Hz, 2H),3.76-3.69 (m, 2H), 3.27-3.21 (m, 2H), 2.41 (s, 3H).

Example 783-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine

Step A: Preparation of (5-Methyl-2-trifluoromethyl-furan-3-yl)-methanol

To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acidethyl ester (0.83 g, 3.7 mmol) in Et₂O at 0° C., was added DIBAL-H (1.0M in THF, 1.5 mL). After 10 min, the ice bath was removed and additionalDIBAL-H was added (1.0 M in THF, 14.5 mL). After 2 h, the reaction wasquenched with a saturated solution of sodium potassium tartrate (aq.)and allowed to stir overnight. After 18 h, EtOAc was added and theorganic layer separated and dried provide the title compound (0.39 g,58%). ¹H NMR (CDCl₃): 6.19 (s, 1H), 4.62 (s, 2H), 2.36-2.28 (m, 3H).

Step B: Preparation of3-[5-chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

Synthesized from the title compound of Step A and3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester using general procedure 7. MS (ESI): mass calcd. forC₂₁H₂₃ClF₃NO₅, 461.1; m/z found, 485.9 [M+Na]⁺. ¹H NMR 6.91 (dd, J=8.6,2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.22 (s,1H), 5.07-5.00 (m, 2H), 4.90-4.81 (m, 1H), 4.30 (ddd, J=9.7, 6.5, 0.8Hz, 2H), 4.06 (dd, J=9.8, 4.0 Hz, 2H), 2.34 (s, 3H), 1.45 (s, 9H).

Step C: Preparation of3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine

Synthesized from the title compound of Step B using general procedure 1.MS (ESI): mass calcd. for C₁₆H₁₅ClF₃NO₃, 361.1; m/z found, 362.1 [M+H]⁺.¹H NMR (CDCl₃): 6.86 (dd, J=8.6, 2.2 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H),6.58 (d, J=2.2 Hz, 1H), 6.23 (s, 1H), 5.03 (s, 2H), 5.01-4.93 (m, 1H),4.01-3.77 (m, 4H), 2.33 (s, 3H).

Example 792-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine

Step A: Preparation of (6-Trifluoromethyl-pyridin-2-yl)-methanol

To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (500 mg, 3mmol) in dry THF at 0° C., was added triethylamine (0.36 mL, 2.6 mmol)followed by ethyl chloroformate (0.25 mL, 2.6 mmol). After 30 min, LiBH₄(2 M in THF, 3.3 mL, 6.5 mmol) was added. After an additional 30 min,the ice bath was removed. After 1 h, the reaction was cooled to 0° C.and quenched with MeOH followed by 1N NaOH and EtOAc. The pH of thesolution was adjusted to pH=5 with 1 N HCl and the mixture extractedwith EtOAc (2×). The combined organic fractions were dried to providethe title compound that was used without further purification. ¹H NMR(CDCl₃): 7.89 (dd, J=7.8, 7.8 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.51 (d,J=7.9 Hz, 1H), 4.85 (s, 2H).

Step B: Preparation of3-[5-Chloro-2-(6-trifluoromethyl-pyridin-2-ylmethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

Prepared from the title compound of Step A and3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester using general procedure 7.

Step C: Preparation of2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine

Prepared from the title compound of Step B according to generalprocedure 1. MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found,359.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.92 (dd, J=7.8, 7.8 Hz, 1H), 7.81 (d,J=7.9 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 6.87 (dd, J=8.6, 2.1 Hz, 1H),6.61 (d, J=2.1, 1H), 5.29 (s, 2H), 5.21-4.99 (m, 1H), 4.21-1.15 (br m,4H).

Examples 80-89 were prepared using the appropriate alcohol and phenolaccording to general procedure 7.

Example 803-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₇H₁₆ClF₃N₂O₂, 372.1; m/z found, 373.0[M+H]⁺. ¹H NMR (CDCl₃): 7.93 (d, J=7.9 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H),6.89 (dd, J=8.6, 2.2 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.2 Hz,1H), 5.11 (s, 2H), 5.03-4.92 (m, 1H), 4.08-3.69 (m, 4H), 2.66 (s, 3H).

Example 812-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found, 358.9[M+H]⁺. ¹H NMR (CDCl₃): 8.86 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.73 (d,J=8.2 Hz, 1H), 6.87 (dd, J=8.6, 2.1 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H),6.61 (d, J=1.9 Hz, 1H), 5.28 (s, 2H), 5.08-4.98 (m, 1H), 4.08-3.97 (m,2H), 3.96-3.85 (m, 2H).

Example 825-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found, 359.0[M+H]⁺. ¹H NMR (CDCl₃): 8.81 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.72 (d,J=8.1 Hz, 1H), 6.90 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H),6.60 (d, J=2.2 Hz, 1H), 5.18 (s, 2H), 5.03-4.95 (m, 1H), 4.02-3.95 (m,2H), 3.89-3.82 (m, 2H).

Example 83 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClNO₃, 329.1; m/z found, 330.1 [M+H]⁺.¹H NMR (CDCl₃): 7.65-7.64 (m, 2H) 7.50 (d, J=8.5 Hz, 1H), 7.35 (dd,J=8.5, 1.6 Hz, 1H), 6.87-6.82 (m, 2H), 6.76 (d, J=1.3 Hz, 1H), 6.59 (s,1H), 5.18 (s, 2H), 5.02-4.92 (m, 1H), 4.06-3.79 (m, 4H).

Example 84 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S, 346.1; m/z found, 347.0 [M+H]⁺.¹H NMR (CDCl₃): 9.01 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.57(dd, J=8.4, 1.6 Hz, 1H), 6.85 (d, J=1.2 Hz, 2H), 6.60 (s, 1H), 5.35 (s,2H), 5.00-4.98 (m, 1H), 3.93-3.87 (m, 4H).

Example 856-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1-methyl-1H-benzotriazole

MS (ESI): mass calcd. for C₁₇H₁₇ClN₄O₂, 344.1; m/z found, 345.0 [M+H]⁺.¹H NMR (CDCl₃): 8.10 (s, 1H), 7.61 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (d,J=8.6 Hz, 1H), 6.88-6.80 (m, 2H), 6.59 (d, J=1.9 Hz, 1H), 5.26 (s, 2H),5.02-4.96 (m, 1H), 4.31 (s, 3H), 3.97-3.82 (m, 4H).

Example 863-[5-Chloro-2-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄ClF₂NO₄, 369.1; m/z found, 370.0 [M+H]⁺.¹H NMR (CDCl₃): 7.20 (d, J=1.2 Hz, 1H), 7.11 (dd, J=8.2, 1.5 Hz, 1H),7.04 (d, J=8.2 Hz, 1H), 6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz,1H), 6.59 (d, J=2.3 Hz, 1H), 5.06 (s, 2H), 5.01-4.95 (m, 1H), 3.96-3.83(m, 4H).

Example 87 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxvmethyl]-oxazole

MS (ESI): mass calcd. for C₁₃H₁₃ClN₂O₃, 280.1; m/z found, 281.1 [M+H]⁺.¹H NMR (CDCl₃): 7.91 (s, 1H), 7.13 (s, 1H), 6.90-6.87 (m, 2H), 6.59 (d,J=1.9 Hz, 1H), 5.10 (s, 2H), 5.00-4.91 (m, 1H), 3.97-3.89 (m, 2H),3.87-3.79 (m, 2H).

Example 88 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole

MS (ESI): mass calcd. for C₁₃H₁₃ClN₂O₂S, 296.0; m/z found, 297.0 [M+H]⁺.¹H NMR (CDCl₃): 7.80 (t, J=3.1 Hz, 1H), 7.38 (t, J=3.3 Hz, 1H),6.96-6.84 (m, 2H), 6.63 (dd, J=11.1, 2.3 Hz, 1H), 5.41-5.37 (m, 2H),5.04-4.78 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.83 (m, 2H), 3.31-3.23 (m,1H)

Example 89 3-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClNO₃, 329.1; m/z found, 330.0 [M+H]⁺.¹H NMR (CDCl₃): 7.56 (d, J=7.7 Hz, 1H), 7.50 (dd, J=8.2, 0.7 Hz, 1H),7.34-7.28 (m, 1H), 7.23 (dt, J=7.5, 1.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H),6.87 (dd, J=8.6, 2.4 Hz, 1H), 6.73 (d, J=0.5 Hz, 1H), 6.57 (d, J=2.4 Hz,1H), 5.17 (s, 2H), 4.95-4.89 (m, 1H), 3.93-3.69 (m, 4H).

Example 90 (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine

Step A: Preparation of3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1-carboxylic acid tert-butylester

To (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g,10.9 mmol) in CH₂Cl₂ (50 mL) at 0° C. was added Et₃N (1.4 g, 1.9 mL,13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 mL, 12.1 mmol).After 1 h, brine was added and the mixture extracted with CH₂Cl₂ (2×).The combined organics were dried to give3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester thatwas used without further purification.

To this compound in DMF (50 mL) was added5-chloro-2-hydroxy-benzaldehyde (1.9 g, 12.1 mmol) and K₂CO₃ (1.8 g,13.1 mmol). The reaction was heated at 90° C. for 2 h, then cooled to rtand H₂O was added. The mixture was extracted with EtOAc (2×). Thecombined organics were washed with brine and dried. Silica gelchromatography (10-50% EtOAc in hexanes) gave 1.85 g (52%) of the titlecompound. ¹H NMR (CDCl₃): 10.36 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H),6.90 (d, J=8.9 Hz, 1H), 5.00 (s, 1H), 3.72-3.50 (m, 4H), 2.26-2.18 (m,2H), 1.47 (s, 9H).

Step B: Preparation of3-(4-chloro-2-hydroxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butylester

To a CH₂Cl₂ (25 mL) solution of the title compound of Step A (1.4 g, 4.3mmol) was added 77% m-CPBA (1.4 g, 6.2 mmol). After 18 h, additionalCH₂Cl₂ was added and the reaction washed with saturated NaHCO₃ (aq.) and10% Na₂S₂O₅ until KI paper negative. The combined organic layers weredried then treated with MeOH (25 mL) and 1N NaOH (25 mL). After 15 h,the reaction was acidified with 1M KHSO₄ then extracted with EtOAc (2×).The combined organic layers were washed with brine and dried to give thetitle compound as a white solid. ¹H NMR (CDCl₃): 6.96 (s, 1H), 6.82-6.80(m, 1H), 6.73 (d, J=8.6 Hz, 1H), 5.62 (s, 1H), 4.91 (s, 1H), 3.66-3.46(m, 4H), 2.20-2.11 (m, 2H), 1.47 (s, 9H).

Step C: Preparation of3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine-1-carboxylic acidtert-butyl ester

Prepared according to Example 1 Step D using the title compound of StepB. MS (ESI): mass calcd. for C₂₂H₂₆ClNO₄, 403.2; m/z found, 426.2[M+Na]⁺, 348.2 [M−56]⁺. ¹H NMR (CDCl₃): 7.43-7.36 (m, 4H), 7.35-7.30 (m,1H), 6.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.5, 2.4 Hz, 1H), 6.82 (d,J=8.5 Hz, 1H), 5.07 (s, 2H), 4.89-4.85 (m, 1H), 3.71-3.45 (m, 4H),2.24-2.12 (m, 1H), 2.07-1.94 (m, 1H), 1.46 (s, 9H).

Step D: Preparation of (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine

Prepared according to general procedure 1 using the title compound ofStep C. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2[M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.36 (m, 4H), 7.35-7.30 (m, 1H), 6.94 (d,J=2.4 Hz, 1H), 6.88 (dd, J=8.6, 2.4 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H),5.06 (s, 2H), 4.86 (s, 1H), 3.25 (d, J=2.1 Hz, 2H), 2.25-1.73 (m, 4H).

Example 91 (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine

Synthesized from the title compound of Example 90 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found,318.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.32 (m, 5H), 6.91 (d, J=2.3 Hz, 1H),6.86 (dd, J=8.5, 2.4 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 5.08 (s, 2H), 4.81(td, J=10.4, 5.1 Hz, 1H), 2.90 (dd, J=10.1, 6.1 Hz, 1H), 2.74 (d, J=8.9Hz, 2H), 2.53 (dd, J=13.8, 7.9 Hz, 1H), 2.38 (s, 3H), 2.28-2.21 (m, 1H),2.08-1.98 (m, 1H).

Example 92 (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

Synthesized according to Example 90 using 3-chlorobenzyl bromide. MS(ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.40 (s, 1H), 7.29-7.20 (m, 3H), 6.86 (dd, J=7.1, 2.2 Hz,2H), 6.79-6.74 (m, 1H), 4.99 (s, 2H), 4.77 (t, J=5.1 Hz, 1H), 3.18-3.13(m, 2H), 2.92-2.86 (m, 2H), 2.11-1.81 (m, 2H).

Example 93(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 92 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₈H₁₉Cl₂NO₂, 351.1; m/z found,352.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.47 (s, 1H), 7.30 (s, 3H), 6.88 (dd,J=7.3, 2.2 Hz, 2H), 6.77-6.74 (m, 1H), 5.04 (s, 2H), 4.85-4.73 (m, 1H),2.96-2.86 (m, 1H), 2.79-2.68 (m, 2H), 2.56-2.50 (m, 1H), 2.39 (s, 3H),2.31-2.17 (m, 1H), 2.05-1.95 (m, 1H).

Example 94 (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

Synthesized according to Example 90 using(R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and3-chlorobenzyl bromide. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1;m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.36-7.24 (m,3H), 6.94-6.86 (m, 2H), 6.84-6.78 (m, 1H), 5.08 (s, 2H), 4.81 (t, J=5.0Hz, 1H), 3.26-3.08 (m, 2H), 3.00-2.84 (m, 2H), 2.12-1.91 (m, 2H).

Examples 95-100 were prepared using 1-methyl-pyrrolidin-3-ol and theappropriately substituted phenol (synthesized according to Example 90)according to general procedure 7 using resin bound PPh₃.

Example 95(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.0 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (s, 1H), 7.33-7.24 (m, 3H), 6.98 (dd, J=8.5, 2.3Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.04 (s, 2H),4.82 (m, 1H), 2.95 (dd, J=10.5, 6.1 Hz, 1H), 2.82-2.73 (m, 2H), 2.55 (m,1H), 2.41 (s, 3H), 2.31 (m, 1H), 2.10-2.00 (m, 1H).

Example 96(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₉H₂₂BrNO₃, 391.1; m/z found, 391.1 [M+H]⁺.¹H NMR (CDCl₃): 7.31-7.23 (m, 1H), 6.99-6.96 (m, 3H), 6.93 (d, J=2.3 Hz,1H), 6.87-6.82 (m, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.06 (s, 2H), 4.86-4.79(m, 1H), 3.81 (s, 3H), 2.94 (dd, J=10.6, 6.1 Hz, 1H), 2.79-2.73 (m, 2H),2.54 (m, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.05 (m, 1H).

Example 97(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-D₆): 7.32 (m, 1H), 7.17 (d, J=7.3 Hz, 2H),7.02-6.96 (m, 2H), 6.94 (d, J=2.3 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.07(s, 2H), 4.82 (m, 1H), 2.94 (m, 1H), 2.82-2.73 (m, 2H), 2.55 (m, 1H),2.40 (s, 3H), 2.31 (m, 1H), 2.07-2.02 (m, 1H).

Example 98 (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₂₀BrNO₂, 361.1; m/z found, 362.1 [M+H]⁺.¹H NMR (CDCl₃): 7.41 (m, 2H), 7.39-7.34 (m, 2H), 7.30 (m, 1H), 6.97 (dd,J=8.5, 2.3 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 5.08(s, 2H), 4.86-4.76 (m, 1H), 2.93 (m, 1H), 2.80-2.72 (m, 2H), 2.57-2.50(m, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.09-1.99 (m, 1H).

Example 99 (±)-Methanesulfonic acid3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester

MS (ESI): mass calcd. for C₁₉H₂₂BrNO₅S, 455.1; m/z found, 456.1 [M+H]⁺.¹H NMR (CDCl₃): 7.46-7.35 (m, 3H), 7.23 (m, 1H), 6.98 (dd, J=8.5, 2.3Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.08 (s, 2H),4.81 (m, 1H), 3.13 (s, 3H), 2.89 (m, 1H), 2.82-2.74 (m, 2H), 2.55-2.46(m, 1H), 2.39 (s, 3H), 2.31 (m, 1H), 2.03 (m, 1H).

Example 100 (±)-Methanesulfonic acid3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester

MS (ESI): mass calcd. for C₁₉H₂₃NO₅S, 377.1; m/z found, 378.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.42 (m, 3H), 7.26-7.20 (m, 1H), 6.98-6.80 (m, 4H), 5.13(s, 2H), 4.86 (m, 1H), 3.12 (s, 3H), 2.93 (dd, J=10.5, 6.1 Hz, 1H),2.81-2.71 (m, 2H), 2.60-2.49 (m, 1H), 2.40 (s, 3H), 2.30 (m, 1H),2.11-2.00 (m, 1H).

Example 101(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Step A: Preparation of(R)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To (S)-1-(3-trifluoromethyl-phenyl)-ethanol (2.30 g, 12.1 mmol),3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (3.80 g, 12.7 mmol) and PPh₃ (3.80 g, 14.5 mmol) in THF (60 mL) at0° C. was added DEAD (2.3 g, 2.1 mL, 13 mmol) in THF (10 mL) dropwiseover 30 min. After 48 h, the reaction was concentrated and 15% EtOAc inhexanes was added. The flask was cooled to 0° C. and filtered. Thefiltrate was concentrated and this procedure repeated 2 more times. Theresulting oil was then purified using silica gel chromatography (10-40%EtOAc in hexanes) to give 5.17 g (91%) of the title compound as a clearoil. ¹H NMR (CDCl₃): 7.66 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (t, J=7.7 Hz,1H), 6.79 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.52 (d,J=2.4 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.88-4.82 (m, 1H), 4.33-4.29 (m,2H), 4.08-4.01 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.46 (s, 9H).

Step B: Preparation of(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

To the title compound of Step A (5.1 g, 10.8 mmol) in CH₂Cl₂ (50 mL) at0° C. was added TFA (50 mL). After 1 h, PhCH₃ (50 mL) was added and themixture concentrated. The resulting oil was neutralized with saturatedNaHCO₃ (aq.) and extracted with CH₂Cl₂ (2×). The combined organics weredried and concentrated. Silica gel chromatography (1-7% 2M NH₃/MeOH inCH₂Cl₂) gave 3.38 g (83% yield) of the title compound as a clear oil. MS(ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺. ¹HNMR (CDCl₃): 7.70 (s, 1H), 7.56-7.53 (m, 2H), 7.45 (t, J=7.7 Hz, 1H),6.77 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz,1H), 5.30 (q, J=6.3 Hz, 1H), 5.00-4.94 (m, 1H), 3.97-3.93 (m, 2H),3.89-3.81 (m, 2H), 1.66 (d, J=6.5 Hz, 3H).

Unless otherwise specified the compounds in Examples 102-144 wereprepared similar to Example 101 using the appropriately substitutedphenols and alcohols.

Example 102(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidinetrifluoroacetate

Prepared using (R)-1-(3-trifluoromethyl-phenyl)-ethanol. MS (ESI): masscalcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺. ¹H NMR(CDCl₃): 7.61 (s, 1H), 7.55-7.45 (m, 3H), 6.86 (dd, J=8.7, 2.2 Hz, 1H),6.68-6.66 (m, 2H), 5.30 (q, J=6.3 Hz, 1H), 5.11 (s, 1H), 4.44-4.32 (m,4H), 1.66 (d, J=6.4 Hz, 3H).

Example 103(S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine

Prepared according to general procedure 5 using the title compound ofExample 102. MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found,386.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=8.0 Hz, 2H), 7.45(t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H),6.59 (d, J=2.3 Hz, 1H), 5.29 (q, J=6.4 Hz, 1H), 4.76-4.65 (m, 1H), 3.85(s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J=6.5 Hz, 3H).

Example 104(S)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared according to general procedure 3 or 4 using the title compoundof Example 102. MS (ESI): mass calcd. for C₂₅H₂₃ClF₃NO₂, 461.1; m/zfound, 462.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=7.1 Hz,2H), 7.45 (t, J=7.7 Hz, 1H), 7.37-7.23 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz,1H), 6.69 (d, J=8.6 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.5 Hz,1H), 4.80-4.71 (m, 1H), 3.85-3.80 (m, 2H), 3.71 (s, 2H), 3.24-3.14 (m,2H), 1.66 (d, J=6.5 Hz, 3H).

Example 105(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.1 [M+H]⁺.¹H NMR (CDCl₃): 7.61 (s, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.51-7.45 (m, 1H),6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.67 (s, 1H), 6.66 (d, J=7.1 Hz, 1H), 5.31(q, J=6.4 Hz, 1H), 5.13-5.09 (m, 1H), 4.58-4.30 (m, 4H), 1.67 (d, J=6.5Hz, 3H).

Example 106(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-isopropyl-azetidine

Synthesized from the title compound of Example 105 according to generalprocedure 3. MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found,414.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (s, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.45(t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H),6.62 (d, J=2.4 Hz, 1H), 5.28 (q, J=6.5 Hz, 1H), 4.75-4.69 (m, 1H),3.86-3.82 (m, 2H), 3.11-3.04 (m, 2H), 2.40 (td, J=12.4, 6.2 Hz, 1H),1.65 (d, J=6.5 Hz, 3H), 0.98 (dd, J=6.2, 0.8 Hz, 6H).

Example 107(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-cyclobutyl-azetidine

Synthesized from the title compound of Example 105 according to generalprocedure 3. MS (ESI): mass calcd. for C₂₂H₂₃ClF₃NO₂, 425.1; m/z found,426.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (s, 1H), 7.55 (t, J=8.7 Hz, 2H), 7.45(t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H),6.61 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.4 Hz, 1H), 4.78-4.72 (m, 1H), 3.75(dd, J=8.5, 6.1 Hz, 2H), 3.26-3.09 (m, 3H), 2.07-1.94 (m, 2H), 1.92-1.68(m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 108(±)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Synthesized from the title compound of Example 105 according to generalprocedure 3. MS (ESI): mass calcd. for C₂₅H₂₃ClF₃NO₂, 461.1; m/z found,462.0 [M+H]⁺. ¹H NMR (CDC₃): 7.69 (s, 1H), 7.54 (t, J=7.4 Hz, 2H), 7.44(t, J=7.7 Hz, 1H), 7.37-7.22 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.69(d, J=8.6 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.4 Hz, 1H),4.79-4.73 (m, 1H), 3.86-3.79 (m, 2H), 3.70 (s, 2H), 3.24-3.13 (m, 2H),1.66 (d, J=6.5 Hz, 3H).

Example 109(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 105 according to generalprocedure 5. MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found,386.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=8.5 Hz, 2H), 7.45(t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H),6.60 (d, J=2.3 Hz, 1H), 5.29 (q, J=6.4 Hz, 1H), 4.74-4.68 (m, 1H), 3.85(s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J=6.5 Hz, 3H).

Example 110(±)-3-[5-Bromo-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₃, 431.0; m/z found, 431.9 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (t, J=8.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.12 (d,J=8.1 Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H),6.64 (d, J=8.6 Hz, 1H), 5.25 (q, J=6.5 Hz, 1H), 5.01-4.93 (m, 1H),4.01-3.80 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 111(±)-3-[5-Bromo-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/z found, 382.0 [M+H]⁺.¹H NMR (CDCl₃): 7.42 (s, 1H), 7.29-7.19 (m, 3H), 6.90 (dd, J=8.6, 2.3Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.20 (q, J=6.4Hz, 1H)), 5.00-4.92 (m, 1H), 3.95-3.80 (m, 4H), 1.64 (d, J=6.5 Hz, 3H).

Example 112(±)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 415.0; m/z found, 416.0 [M+H]⁺.¹H NMR (CDCl₃): 7.69 (s, 1H), 7.53 (t, J=7.3 Hz, 2H), 7.44 (t, J=7.7 Hz,1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.65 (d,J=8.6 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.95-3.92 (m,2H), 3.87-3.80 (m, 2H), 1.65 (d, J=6.5 Hz, 3H).

Example 113(R)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 415.0; m/z found, 418.0 [M+H]⁺.¹H NMR (CDCl₃): 7.69 (s, 1H), 7.58-7.50 (m, 2H), 7.45 (t, J=7.7 Hz, 1H),6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.66 (d, J=8.6 Hz,1H), 5.30 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 4.01-3.74 (m, 4H), 1.67(d, J=6.5 Hz, 3H).

Example 114(±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxly]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺.¹H NMR (CDCl₃): 7.43 (s, 1H), 7.32-7.17 (m, 3H), 6.76 (dd, J=8.6, 2.4Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.20 (q, J=6.5Hz, 1H), 5.02-4.92 (m, 1H), 3.94 (s, 2H), 3.92-3.78 (m, 2H), 1.65 (d,J=6.5 Hz, 3H).

Example 115(±)-3-[5-Chloro-2-[1-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.1 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.23 (m, 1H), 7.21-7.07 (m, 2H), 7.00-6.91 (m, 1H),6.71-6.65 (m, 2H), 6.64-6.52 (m, 1H), 5.28-5.18 (m, 1H), 5.05-4.93 (m,1H), 4.10-3.95 (s, 4H), 1.70-1.60 (s, 3H).

Example 116(±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.0 [M+H]⁺.¹H NMR (CDCl₃): 7.55 (dd, J=7.6, 1.8 Hz, 1H), 7.34 (dd, J=7.8, 1.4 Hz,1H), 7.28-7.14 (m, 2H), 6.73 (dd, J=8.6, 2.4 Hz, 1H), 6.59 (d, J=8.7 Hz,1H), 6.56 (d, J=2.4 Hz, 1H), 5.66 (q, J=6.4 Hz, 1H), 5.00-4.94 (m, 1H),4.02-3.81 (m, 4H), 1.64 (d, J=6.4 Hz, 3H).

Example 117(±)-3-[5-Chloro-2-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺.¹H NMR (CDCl₃): 7.68 (dd, J=6.7, 1.9 Hz, 1H), 7.58-7.51 (m, 1H),7.19-7.14 (m, 1H), 6.78 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H),6.55 (d, J=2.3 Hz, 1H), 5.27 (q, J=6.4 Hz, 1H), 4.95-4.90 (m, 1H),3.95-3.84 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 118(±)-3-[5-Chloro-2-[1-(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺.¹H NMR (CDCl₃): 7.57 (t, J=7.6 Hz, 1H), 7.31-7.22 (m, 2H), 6.77 (dd,J=8.6, 2.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.26(q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.97-3.80 (m, 4H), 1.65 (d, J=6.5Hz, 3H).

Example 119(±)-3-[5-Chloro-2-[1-(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺.¹H NMR (CDCl₃): 7.33 (d, J=9.3 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.79(dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H),5.28 (q, J=6.5 Hz, 1H), 4.99-4.92 (m, 1H), 7.47 (s, 1H), 4.05-3.74 (m,4H), 1.66 (d, J=6.5 Hz, 3H).

Example 120(±)-3-[5-Chloro-2-[1-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂S, 403.1; m/z found, 404.0[M+H]⁺. ¹H NMR (CDCl₃): 7.70 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.49 (d,J=7.8 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 6.75 (dd, J=8.6, 2.3 Hz, 1H),6.68 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.2 Hz, 1H), 5.26 (q, J=6.5 Hz, 1H),4.99-4.93 (m, 1H), 3.94-3.83 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 121(±)-3-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.0 [M+H]⁺.¹H NMR (CDCl₃): 7.50 (dt, J=7.6, 1.7 Hz, 1H), 7.24-7.21 (m, 1H), 7.12(dt, J=7.6, 1.0 Hz, 1H), 7.06-6.99 (m, 1H), 6.75 (dd, J=8.6, 2.3 Hz,1H), 6.69 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.60 (q, J=6.4 Hz,1H), 5.00-4.94 (m, 1H), 4.00-3.79 (m, 4H), 1.67 (d, J=6.4 Hz, 3H).

Example 122(±)-3-[5-Chloro-2-[1-(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺.¹H NMR (CDCl₃): 7.85 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.56 (t,J=7.7 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 6.72 (dd, J=8.6, 2.3 Hz, 1H),6.67 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 5.68 (q, J=6.2 Hz, 1H),5.00-4.94 (m, 1H), 4.01-3.79 (m, 4H), 1.66 (d, J=6.3 Hz, 3H).

Example 123(±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.0 [M+H]⁺.¹H NMR (CDCl₃): 7.30 (s, 4H), 6.74 (dd, J=8.6, 2.4 Hz, 1H), 6.65 (d,J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.21 (q, J=6.5 Hz, 1H), 4.99-4.93(m, 1H), 3.96-3.83 (m, 4H), 1.64 (d, J=6.5 Hz, 3H).

Example 124(±)-3-[5-Chloro-2-[1-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.0 [M+H]⁺.¹H NMR (CDCl₃): 7.39-7.29 (m, 2H), 7.06-6.97 (m, 2H), 6.74 (dd, J=8.6,2.4 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.22 (q,J=6.4 Hz, 1H), 4.99-4.93 (m, 1H), 3.99-3.78 (m, 4H), 1.64 (d, J=6.4 Hz,3H).

Example 125(±)-3-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₂, 328.1; m/z found, 329.1 [M+H]⁺.¹H NMR (CDCl₃): 7.76 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.57 (td, J=7.7,1.3 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69(d, J=8.6 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.27 (q, J=6.6 Hz, 1H),5.01-4.95 (m, 1H), 4.02-3.76 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 126(±)-3-[5-Chloro-2-[1-(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₆Cl₃NO₂, 371.0; m/z found, 372.0 [M+H]⁺.¹H NMR (CDCl₃): 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.19(dd, J=8.3, 2.0 Hz, 1H), 6.77 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.18 (q, J=6.5 Hz, 1H), 4.99-4.93 (m,1H), 4.00-3.76 (m, 4H), 1.63 (d, J=6.5 Hz, 3H).

Example 127(±)-3-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₃, 387.1; m/z found, 388.0 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (t, J=8.1 Hz, 1H), 7.30-7.27 (m, 2H), 7.16-7.08 (m,1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.55 (d,J=2.4 Hz, 1H), 5.25 (q, J=6.4 Hz, 1H), 5.00-4.93 (m, 1H), 3.98-3.77 (m,4H), 1.65 (d, J=6.5 Hz, 3H).

Example 128(±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.1 [M+H]⁺.¹H NMR (CDCl₃): 7.21-7.09 (m, 2H), 7.08-7.02 (m, 1H), 6.85 (dd, J=8.7,2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 5.20 (q,J=6.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.44-4.32 (m, 4H), 1.62 (d, J=6.4 Hz,3H).

Example 129(±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆Cl₃NO₂, 371.0; m/z found, 372.0 [M+H]⁺.¹H NMR (CDCl₃): 7.43 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.19(dd, J=8.5, 2.5 Hz, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=2.4Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.59 (q, J=6.3 Hz 1H), 5.14 (s, 1H),4.49-4.37 (m, 4H), 1.63 (d, J=6.4 Hz, 3H).

Example 130(±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.0 [M+H]⁺.¹H NMR (CDCl₃): 7.43 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.19(dd, J=8.5, 2.5 Hz, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=2.4Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.59 (q, J=6.3 Hz, 1H), 5.14 (s, 1H),4.47-4.34 (m, 4H), 1.63 (d, J=6.4 Hz, 3H).

Example 1312-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole

MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₂S, 360.1; m/z found, 361.0 [M+H]⁺.¹H NMR (CDCl₃): 8.01-7.99 (m, 1H), 7.92-7.86 (m, 1H), 7.48 (ddd, J=8.3,7.3, 1.3 Hz, 1H), 7.39 (ddd, J=8.3, 7.3, 1.2 Hz, 1H), 6.93 (d, J=8.6 Hz,1H), 6.80 (dd, J=8.6, 2.4 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 5.66 (q,J=6.5 Hz, 1H), 5.01-4.95 (m, 1H), 3.95-3.88 (m, 2H), 3.86-3.80 (m, 2H),1.86 (d, J=6.5 Hz, 3H).

Example 132 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₂S, 310.1; m/z found, 311.0 [M+H]⁺.¹H NMR (CDCl₃): 8.77 (s, 1H), 7.73 (s, 1H), 6.83-6.77 (m, 2H), 6.57-6.56(m, 1H), 5.56 (q, J=6.4 Hz, 1H), 5.02-4.89 (m, 1H), 3.98-3.90 (m, 2H),3.87-3.75 (m, 2H), 1.77 (d, J=6.4 Hz, 3H).

Example 133 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₂S, 310.1; m/z found, 311.1 [M+H]⁺.¹H NMR (CDCl₃): 7.74 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 6.88 (d,J=8.6 Hz, 1H), 6.81 (dd, J=8.6, 2.3 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H),5.59 (q, J=6.5 Hz, 1H), 5.02-4.92 (m, 1H), 4.04-3.72 (m, 4H), 1.79 (dd,J=6.4, 2.2 Hz, 3H).

Example 1345-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole

MS (ESI): mass calcd. for C₁₆H₁₉ClN₂O₂S, 338.1; m/z found, 339.1 [M+H]₊.¹H NMR (CDCl₃): 6.78 (dd, J=8.5, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H),6.55 (d, J=2.4 Hz, 1H), 5.48 (q, J=6.4 Hz, 1H), 5.00-4.90 (m, 1H),4.02-3.76 (m, 4H), 2.63 (s, 3H), 2.19 (s, 3H), 1.69 (d, J=6.4 Hz, 3H).

Example 135(R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₂, 399.1; m/z found, 400.0 [M+H]⁺.¹H NMR (CDCl₃): 7.68 (s, 1H), 7.57-7.52 (m, 2H), 7.45 (t, J=7.7 Hz, 1H),6.90 (d, J=2.4 Hz, 1H), 6.77 (d, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz,1H), 5.30 (q, J=6.4 Hz, 1H), 4.36-4.32 (m, 1H), 3.17 (br s, 2H), 2.74(br s, 2H), 2.02 (br s, 2H), 1.72 (br s, 2H), 1.64 (d, J=6.4 Hz, 3H).

Example 136(±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁Cl₂NO₂, 349.1; m/z found, 350.1 [M+H]⁺.¹H NMR (CDCl₃): 7.40 (s, 1H), 7.29-7.19 (m, 3H), 6.89 (d, J=2.4 Hz, 1H),6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 5.21 (q, J=6.4 Hz,1H), 4.38-4.27 (m, 1H), 3.17 (td, J=7.8, 4.6 Hz, 2H), 2.72 (ddd, J=12.5,9.3, 3.2 Hz, 2H), 2.09-1.93 (m, 2H), 1.79-1.66 (m, 2H), 1.62 (d, J=6.5Hz, 3H).

Example 137(±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₃, 415.1; m/z found, 416.0 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (t, J=7.9 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.12 (d,J=8.0 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H),6.68 (d, J=8.6 Hz, 1H), 5.26 (q, J=6.4 Hz, 1H), 4.43-4.24 (m, 1H),3.22-3.09 (m, 2H), 2.73 (ddd, J=12.5, 9.2, 3.1 Hz, 2H), 2.02 (d, J=9.1Hz, 2H), 1.72 (dt, J=12.7, 9.0, 2H), 1.63 (d, J=6.4 Hz, 3H).

Example 138(±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.1; m/z found, 350.0 [M+H]⁺.¹H NMR (CDCl₃): 7.50 (dt, J=7.6, 1.7 Hz, 1H), 7.26-7.20 (m, 1H), 7.12(dt, J=7.5, 1.0 Hz, 1H), 7.02 (ddd, J=10.2, 8.2, 1.1 Hz, 1H), 6.89 (d,J=2.4 Hz, 1H), 6.76 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H),5.59 (q, J=6.4 Hz, 1H), 4.38-4.27 (m, 1H), 3.16 (td, J=9.8, 4.6 Hz, 2H),2.71 (ddd, J=12.4, 9.3, 3.1 Hz, 2H), 2.01 (ddd, J=13.2, 5.0, 3.0 Hz,2H), 1.72 (ddt, J=11.7, 8.3, 3.1 Hz, 2H), 1.64 (d, J=6.4 Hz, 3H).

Example 139(R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₂, 399.1; m/z found, 400.0 [M+H]⁺.¹H NMR (CDCl₃): 7.68 (s, 1H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 1H), 6.92(dd, J=2.4, 1.1 Hz, 1H), 6.79-6.76 (m, 1H), 6.69 (dd, J=8.6, 6.1 Hz,1H), 5.33-5.26 (m, 1H), 4.24-4.17 (m, 1H), 3.14-3.11 (m, 1H), 2.89-2.73(m, 3H), 2.05-1.98 (m, 1H), 1.87-1.73 (m, 2H), 1.64 (d, J=6.5 Hz, 3H),1.54-1.45 (m, 1H).

Example 140(±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine

MS (ESI): MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found,386.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.66 (s, 1H), 7.52 (t, J=7.5 Hz, 2H), 7.44(t, J=7.7 Hz, 1H), 6.73 (dd, J=8.6, 2.4 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H),6.54 (d, J=2.4 Hz, 1H), 5.05-5.00 (m, 1H), 4.99-4.92 (m, 1H), 4.01-3.72(m, 4H), 2.31-1.97 (m, 1H), 1.97-1.83 (m, 1H), 1.02 (t, J=7.4 Hz, 3H).

Example 141(±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found, 414.0 [M+H]⁺.¹H NMR (CDCl₃): 7.61 (s, 1H), 7.51 (dd, J=7.4, 4.4 Hz, 2H), 7.47-7.40(m, 1H), 6.88 (d, J=2.5 Hz, 1H), 6.72 (dd, J=8.6, 2.5 Hz, 1H), 6.61 (d,J=8.7 Hz, 1H), 5.05 (t, J=6.3 Hz, 1H), 4.37-4.28 (m, 1H), 3.23-3.10 (m,2H), 2.71 (ddd, J=12.6, 9.4, 3.2 Hz, 2H), 2.13-1.97 (m, 3H), 1.96-1.84(m, 1H), 1.76-1.65 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Example 142 3-[5-Bromo-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrFNO₂, 365.0; m/z found, 366.0 [M+H]⁺.¹H NMR (CDCl₃): 7.41-7.30 (m, 5H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 6.69(dd, J=13.3, 5.4 Hz, 2H), 5.35 (ddd, J=14.3, 7.7, 3.3 Hz, 1H), 5.00-4.93(m, 1H), 4.75 (ddd, J=48.0, 10.1, 7.7 Hz, 1H), 4.59 (ddd, J=46.7, 10.1,3.4 Hz, 1H), 3.93-3.79 (m, 4H).

Example 143 3-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.1 [M+H]⁺.¹H NMR (CDCl₃): 7.42-7.31 (m, 5H), 6.75-6.71 (m, 2H), 6.56 (s, 1H), 5.35(ddd, J=14.3, 7.7, 3.3 Hz, 1H), 5.00 (s, 1H), 4.75 (ddd, J=48.0, 10.0,7.7, Hz, 1H), 4.59 (ddd, J=46.7, 10.1, 3.3 Hz, 1H), 4.26-3.53 (m, 4H).

Example 144(±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.1; m/z found, 350.1 [M+H]⁺.¹H NMR (CDCl₃): δ 7.45-7.28 (m, 5H), 6.90 (d, J=2.2 Hz, 1H), 6.77-6.67(m, 2H), 5.36 (ddd, J=14.5, 7.6, 3.3 Hz, 1H), 4.80-4.50 (m, 2H), 4.35(dt, J=12.3, 4.0 Hz, 1H), 3.14 (dd, J=12.0, 4.9 Hz, 2H), 2.70 (dd,J=11.9, 9.7 Hz, 2H), 2.00 (dd, J=7.9, 3.9 Hz, 2H), 1.77-1.62 (m, 2H).

Example 145 (±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine

Step A: Preparation of1-[3-(5-Chloro-2-hydroxy-phenoxy)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (0.80 g, 2.7 mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (5mL). After 18 h, EtOAc was added and the resulting white solid filteredto give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a whitesolid. To a CH₂Cl₂ (25 mL) solution of this compound was added Et₃N(0.30 g, 0.42 mL, 3.0 mmol) and TFAA (0.58 g, 0.38 mL, 2.8 mmol). After18 h, H₂O was added and the reaction extracted with CH₂Cl₂ (2×). Thecombined organics were dried and concentrated to give 0.54 g (74% yield2 steps) of the title compound as a brown oil that was used in the nextstep without further purification.

Step B: Preparation of(±)-1-[3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To the title compound of Step A (0.17 g, 0.56 mmol) in DMF (3 mL) wasadded Cs₂CO₃ (0.25 g, 0.80 mmol), KI (0.09 g, 0.55 mmol) and(1-bromoethyl)-benzene (0.10 g, 0.08 mL, 0.56 mmol). After 15 h, H₂O wasadded and the mixture extracted with EtOAc (2×). The combined organicswere washed with brine and dried. Silica gel chromatography (5-25% EtOAcin hexanes) gave 0.14 g (64%) of the title compound. ¹H NMR (CDCl₃):7.37-7.27 (m, 5H), 6.82 (dd, J=8.7, 2.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H),6.60 (d, J=2.4 Hz, 1H), 5.2 (q, J=6.5 Hz, 1H), 5.0-4.9 (m, 1H),4.75-4.69 (m, 1H), 4.52-4.42 (m, 2H), 4.32-4.21 (m, 1H), 1.67 (d, J=6.4Hz, 3H).

Step C: Preparation of(±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine

To the title compound of Step B in MeOH (4 mL) was added K₂CO₃ (0.10 g,0.72 mmol). After 15 h, H₂O was added and the mixture extracted withEtOAc (2×). The combined organics were dried and concentrated. Silicagel chromatography (1-7 2M NH₃/MeOH in CH₂Cl₂) gave 0.75 g (68% yield)of the title compound. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.10;m/z found, 304.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.31 (m, 4H), 7.28-7.24(m, 1H), 6.72 (dd, J=8.6, 2.4 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.55 (d,J=2.4 Hz, 1H), 5.23 (q, J=6.4 Hz, 1H), 4.99-4.93 (m, 1H), 3.95-3.81 (m,4H), 1.66 (d, J=6.5 Hz, 3H).

Example 146(±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine

Step A: Preparation of 1-(5-Trifluoromethyl-furan-2-yl)-ethanol

To 5-trifluoromethyl-furan-2-carbaldehyde (0.76 g, 4.6 mmol) in THF (20mL) at 0° C. was added MeMgBr (3M in Et₂O, 3 mL, 6 mmol) dropwise over 1h. After an additional 1 h, 1 saturated NH₄Cl (aq.) was added and themixture extracted with EtOAc (2×). The combined organics were washedwith brine and dried to give 0.81 g (97%) of the title compound. ¹H NMR(CDCl₃): 6.74-6.73 (m, 1H), 6.32-6.31 (m, 1H), 4.91 (q, J=6.5 Hz, 1H),1.57 (d, J=6.6 Hz, 3H).

Step B: Preparation of1-(3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidin-1-yl)-2,2,2-trifluoro-ethanone

Prepared from the title compound of Step A and the title compound ofExample 145 Step A using general procedure 7. ¹H NMR (CDCl₃): 6.94 (dd,J=8.6, 2.3 Hz, 1H), 6.88 (dd, J=8.7, 1.4 Hz, 1H), 6.73 (m, 1H), 6.62 (d,J=2.3 Hz, 1H), 6.33 (d, J=3.3 Hz, 1H), 5.27-5.22 (m, 1H), 5.01-4.94 (m,1H), 4.76-4.69 (m, 1H), 4.52-4.44 (m, 2H), 4.27-4.21 (m, 1H), 1.74 (d,J=6.6 Hz, 3H).

Step C: Preparation of(±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine

Prepared from the title compound of Step B according to Example 145 StepC. MS (ESI): mass calcd. for C₁₆H₁₅ClF₃NO₃, 361.1; m/z found, 362.0[M+H]⁺. ¹H NMR (CDC₃): 6.84-6.79 (m, 2H), 6.72-6.71 (m, 1H), 6.57 (d,J=1.9 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 5.24 (q, J=6.6 Hz, 1H), 4.98-4.92(m, 1H), 3.93-3.82 (m, 4H), 1.72 (d, J=6.6 Hz, 3H).

Example 147 3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine

Synthesized according to Example 146 using 1-phenyl-propan-1-ol. MS(ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.33-7.23 (m, 5H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 6.62 (d,J=8.6 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 4.97-4.92 (m, 2H), 4.03-3.78 (m,4H), 2.11-2.02 (m, 1H), 1.95-1.85 (m, 1H), 1.01 (t, J=7.4 Hz, 3H).

Example 148 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol

Step A: Preparation of3-[5-Chloro-2-(methoxycarbonyl-phenyl-methoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (1.1 g, 3.7 mmol) in DMF (18 mL) was added Cs₂CO₃ (1.5 g, 4.4mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 mL, 4.0mmol). After 15 h, H₂O was added and the mixture extracted with EtOAc(2×). The combined organics were washed with brine and dried. Silica gelchromatography (5-25% EtOAc in hexanes) gave 1.6 g (96%) of the titlecompound. ¹H NMR (CDCl₃): 7.55-7.33 (m, 2H), 7.43-7.36 (m, 3H), 6.85 (d,J=1.2, 2H), 6.51 (t, J=1.2 Hz, 1H), 5.58 (s, 1H), 4.91-4.85 (m, 1H),4.31-4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.89-3.74 (m, 3H), 1.46 (s, 9H).

Step B: Preparation of3-[5-Chloro-2-(methoxycarbonyl-phenyl-methoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Step A (0.22 g, 0.50 mmol) in THF at 0° C. wasadded LiBH₄ (2M in THF, 0.4 mL, 0.8 mmol). After 2 h, 1N KHSO₄ (aq.) wasadded and the mixture extracted with EtOAc (2×). The combined organiclayers were washed with brine and dried. Silica gel chromatography(5-25% EtOAc in hexanes) gave 0.17 g (82%) of the title compound. ¹H NMR(CDCl₃): 7.36-7.30 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.68 (d, J=8.7Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 5.09 (dd, J=8.7, 3.4 Hz, 1H), 4.90-4.85(m, 1H), 4.35-4.30 (m, 2H), 4.15-3.94 (m, 4H), 3.80-3.77 (m, 1H), 1.47(s, 9H).

Step C: Preparation of2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol

Prepared from the title compound of Step B according to generalprocedure 1. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found,320.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 7.40 (m, 5H), 6.94-6.69 (m, 3H),5.32-5.28 (m, 1H), 5.11-4.79 (m, 2H), 3.80-3.75 (m, 3H), 3.61 (dd,J=11.4, 4.1 Hz, 1H), 3.54-3.20 (m, 2H).

Example 149 [2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acidhydrochloride

Step A: Preparation of3-[2-(Carboxy-phenyl-methoxy)-5-chloro-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Example 148 Step A (0.16 g, 0.36 mmol) in MeOH(3 mL) was added 1N NaOH (3 mL). After 18 h, the solution was acidifiedwith 1N KHSO₄ and extracted with EtOAc (2×). The combined organics werewashed with brine and dried to give 0.16 g (>98%) of the title compound.¹H NMR (CDCl₃): 8.56-8.19 (broad s, 1H), 7.55-7.51 (m, 2H), 7.41-7.36(m, 3H), 6.85-6.84 (m, 2H), 6.54 (s, 1H), 5.55 (s, 1H), 4.88-4.83 (m,1H), 4.29-4.24 (m, 2H), 4.06-3.97 (m, 2H), 1.44 (s, 9H).

Step B: Preparation of[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid hydrochloride

Prepared from the title compound of Step A according to generalprocedure 1. MS (ESI): mass calcd. for C₁₇H₁₆ClNO₄, 333.1; m/z found,334.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 13.3 (s, 1H), 9.27 (s, 2H), 7.58-7.56(m, 2H), 7.46-7.37 (m, 3H), 7.05-6.99 (m, 2H), 6.96 (d, J=2.2 Hz, 1H),5.86 (s, 1H), 5.11-5.06 (m, 1H), 4.45-4.37 (m, 2H), 4.05-3.98 (m, 2H).

Example 150(±)-3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine

Step A: Preparation of (±)-6-fluoro-indan-1-ol

To a solution of 6-fluoro-indan-1-one (0.50 g, 3.3 mmol) in DCE (10 mL)and MeOH (10 mL) was added NaBH₄ (0.25 g, 6.6 mmol). After 30 min thereaction was quenched with H₂O (10 mL) and extracted with CH₂Cl₂ (3×20mL). The organic layers were combined and dried to give the titlecompound (0.49 g, 97%). MS (ESI): mass calcd. for C₉H₇FO, 150.1; m/zfound, 151.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.23-7.13 (m, 1H), 7.09 (dd, J=8.6,2.5 Hz, 1H), 6.99-6.90 (m, 1H), 5.21 (t, J=6.3 Hz, 1H), 3.13-2.91 (m,1H), 2.85-2.68 (m, 1H), 2.63-2.44 (m, 1H), 2.09-1.74 (m, 2H).

Step B: Preparation of1-[3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidin-1-yl]-2,2,2-trifluoro-ethanone

Prepared from the title compound of Step A and the title compound ofExample 145 Step A according to the general procedure 7.

Step C: Preparation of3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine

Prepared from the title compound of Step B using general procedure 2. MS(ESI): mass calcd. for C₁₈H₁₇ClFNO₂, 333.1; m/z found, 334.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.23 (dd, J=8.2, 5.0 Hz, 1H), 7.10-6.87 (m, 4H), 6.65 (s,1H), 5.68-5.53 (m, 1H), 4.94 (s, 1H), 4.15-4.06 (m, 4H), 3.19-2.99 (m,1H), 2.97-2.66 (m, 1H), 2.67-2.43 (m, 1H), 2.40-2.17 (m, 1H).

Unless otherwise specified the compounds in Examples 151-161 wereprepared according to Example 150 using the appropriately substitutedphenol and alcohol.

Example 151 (±)-3-[5-Bromo-2-(indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈BrNO₂, 359.1; m/z found, 360.0 [M+H]⁺.¹H NMR (CDCl₃): 7.40-7.16 (m, 4H), 7.11 (d, J=8.5 Hz, 1H), 7.05-6.90 (m,2H), 5.67 (d, J=3.4 Hz, 1H), 4.05-3.84 (m, 2H), 3.82-3.52 (m, 2H),3.24-3.10 (m, 1H), 2.93 (d, J=4.5 Hz, 1H), 2.65-2.43 (m, 1H), 2.34-2.17(m, 2H).

Example 152 (±)-3-[5-Bromo-2-(5-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrClNO₂, 393.0; m/z found, 394.0 [M+H]⁺.¹H NMR (CDCl₃): 7.36-7.12 (m, 4H), 7.00-6.87 (m, 1H), 6.79 (s, 1H), 5.65(s, 1H), 4.98-4.74 (m, 1H), 4.46-4.29 (m, 1H), 4.29-4.04 (m, 2H),3.25-3.10 (m, 1H), 3.03-2.83 (m, 1H), 2.60-2.46 (m, 1H), 2.36-2.20 (m,2H).

Example 153 (±)-3-[5-Bromo-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrClNO₂, 393.0; m/z found, 394.0 [M+H]⁺.¹H NMR (CDCl₃): 7.42-7.09 (m, 5H), 7.02-6.83 (m, 1H), 5.62 (s, 1H), 4.38(s, 1H), 4.27-3.90 (m, 2H), 3.73-3.54 (m, 1H), 3.12 (s, 1H), 2.90 (s,1H), 2.53 (s, 1H), 2.35-2.14 (m, 2H).

Example 154 (±)-3-[5-Bromo-2-(5-fluoro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrFNO, 377.0; m/z found, 378.0 [M+H]⁺.¹H NMR (CDCl₃): 7.23 (d, J=5.2, 1H), 7.13-7.03 (m, 1H), 6.98-6.79 (m,4H), 4.95-4.68 (m, 1H), 4.37-3.96 (m, 4H), 3.08 (s, 1H), 2.86 (s, 1H),2.53-2.38 (m, 1H), 2.31-2.11 (m, 2H).

Example 155 (±)-3-[5-Bromo-2-(5-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀BrNO₂, 373.1; m/z found, 374.0 [M+H]⁺.¹H NMR (CDCl₃): 7.25-7.10 (m, 4H), 7.04-6.78 (m, 2H), 5.65 (s, 2H), 4.31(s, 1H), 4.12 (s, 2H), 3.10 (s, 1H), 2.89 (s, 1H), 2.46 (s, 2H), 2.35(d, J=6.6 Hz, 4H).

Example 156 (±)-3-[5-Bromo-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀BrNO₂, 373.1; m/z found, 374.0 [M+H]⁺.¹H NMR (CDCl₃): 7.36-7.18 (m, 3H), 7.08 (d, J=8.2, 1H), 7.02-6.92 (m,2H), 5.67 (d, J=3.4 Hz, 1H), 4.02-3.84 (m, 2H), 3.80-3.53 (m, 2H),3.24-3.10 (m, 1H), 2.93 (d, J=4.5 Hz, 1H), 2.65-2.46 (m, 1H), 2.37-2.18(m, 5H).

Example 157(±)-3-[5-Bromo-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₇BrF₃NO₂, 427.1; m/z found, 429.0 [M+H]⁺.¹H NMR (CDCl₃): 7.69-7.35 (m, 3H), 7.07 (dd, J=8.5, 2.3 Hz, 1H), 6.91(d, J=8.5 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 5.72-5.56 (m, 1H), 4.95 (s,1H), 3.91 (s, 4H), 3.21 (d, J=9.4 Hz, 1H), 3.07-2.85 (m, 1H), 2.61-2.46(m, 1H), 2.42-2.22 (m, 1H).

Example 158(±)-3-[5-Chloro-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.4 [M+H]⁺.¹H NMR (CDCl₃): 7.22-7.08 (m, 3H), 7.02-6.89 (m, 2H), 6.67-6.60 (m, 1H),5.63 (dd, J=6.5, 4.1 Hz, 1H), 4.96-4.86 (m, 1H), 4.04-3.72 (m, 4H),3.21-3.02 (m, 1H), 2.94-2.77 (m, 1H), 2.57-2.40 (m, 1H), 2.33 (d, J=8.2Hz, 3H), 2.29-2.17 (m, 1H).

Example 159(±)-3-[5-Chloro-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇Cl₂NO₂, 349.1; m/z found, 350.0 [M+H]⁺.¹H NMR (CDCl₃): 7.38-7.19 (m, 3H), 7.06-6.93 (m, 2H), 6.76-6.59 (m, 1H),5.74-5.54 (m, 1H), 5.05-4.78 (m, 1H), 4.30-3.89 (m, 3H), 3.13 (d, J=8.2Hz, 1H), 2.91 (d, J=5.1 Hz, 1H), 2.63-2.45 (m, 1H), 2.27 (s, 1H), 2.19(s, 1H).

Example 1603-[5-Chloro-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₇ClF₃NO₂, 383.1; m/z found, 384.1 [M+H]⁺.¹H NMR (CDCl₃): 7.74-7.40 (m, 3H), 7.03-6.88 (m, 2H), 6.65 (d, J=2.2 Hz,1H), 5.73-5.59 (m, 1H), 4.99 (s, 1H), 4.33-3.65 (m, 2H), 3.23 (s, 1H),3.01 (s, 2H), 2.68-2.48 (m, 2H), 2.44-2.31 (m, 1H).

Example 1613-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.2 [M+H]⁺.¹H NMR (CDCl₃): 7.29-7.13 (m, 4H), 7.01 (d, J=8.7 Hz, 3H), 5.27 (s, 1H),4.96-4.71 (m, 1H), 4.08 (s, 3H), 2.91 (s, 1H), 2.79 (s, 1H), 2.19-2.04(m, 4H), 1.86 (s, 1H).

Example 162 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine

Step A: Preparation of 1-(4-tert-Butyl-phenyl)-3-chloro-propan-1-one

To a solution of tert-butyl benzene (1.0 g, 7.5 mmol) and3-chloropropionyl chloride (0.7 mL, 7.5 mmoL) in CH₂Cl₂ (20 mL) wasadded dropwise to a suspension of AlCl₃ (1.1 g, 8.2 mmol) in CH₂Cl₂ (10mL) at 0° C. The reaction was allowed to warm to rt. After 15 h, thereaction was quenched with H₂O (10 mL) and extracted with CH₂Cl₂ (2×20mL). The organic layers were combined and dried to give the titlecompound that was used without further purification (1.3 g).

Step B.: Preparation of 5-tert-butyl-indan-1-one

The title compound of Step A (1.3 g, 5.8 mmol) was dissolved in conc.H₂SO₄ (10 mL) and heated at 95° C. for 3 h. The reaction mixture wascooled to rt, poured onto ice, and extracted with Et₂O (3×25 mL). Thecombined organic extracts were washed with sat'd NaHCO₃ (aq.) and driedto provide the title compound (0.74 g, 68%). MS (ESI): mass calcd. forC₁₃H₁₆O, 188.1; m/z found, 189.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.67-7.58 (m,1H), 7.44-7.32 (m, 2H), 3.09-3.02 (m, 2H), 2.65-2.68 (m, 2H), 1.27 (d,J=8.5 Hz, 9H).

Step B.: Preparation of3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₂H₂₆BrNO₂, 415.1; m/z found, 418.1 [M+H]⁺.¹H NMR (CDCl₃): 7.38-7.13 (m, 4H), 7.08-6.84 (m, 2H), 5.71 (s, 1H), 4.32(s, 2H), 3.71-3.50 (m, 2H), 3.14 (s, 1H), 2.94 (s, 1H), 2.53 (s, 1H),2.24 (s, 2H), 1.43-1.20 (m, 9H).

Example 1633-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine

A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester (0.5 mmol), tetrahydro-furan-3-yl-methanol (0.5 mmol),and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL)was heated at 120° C. in a microwave reactor for 1 h. The mixture wascooled to rt and purified via PTLC providing3-[5-chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester (120 mg). To this compound was added CH₂Cl₂ (20mL) and TFA (3 mL). After 4 h at rt the mixture was concentrated to givethe title compound (161 mg). MS (ESI): mass calcd. for C₁₄H₁₈ClNO₃,283.1; m/z found, 284.0 [M+H]. ¹H NMR (MeOD): 7.05-6.96 (m, 2H), 6.88(d, J=1.9 Hz, 1H), 5.15-5.05 (m, 1H), 4.57-4.48 (m, 2H), 4.28-4.19 (m,2H), 4.04-3.88 (m 4H), 3.82-3.70 (m 2H), 2.82-2.70 (m, 1H), 2.20-2.09(m, 1H), 1.84-1.73 (m, 1H).

The compounds in Examples 164-174 were prepared according to Example 163with the appropriate alcohols.

Example 1643-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.0 [M+H]⁺.¹H NMR (MeOD): 7.18-6.90 (m, 7H), 4.98-4.89 (m, 1H), 4.87-4.78 (m, 1H),4.35-4.25 (m, 2H), 4.12-3.95 (m, 2H), 3.30-2.80 (m, 4H), 2.18-2.02 (m,2H).

Example 165 3-[5-Chloro-2-(chroman-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1[M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.13-6.75 (m, 7H), 5.15-4.98 (m, 1H), 4.55-4.09(m, 7H), 3.00-2.75 (m, 2H), 2.18-1.85 (m, 2H).

Example 1663-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₄H₁₈ClNO₃, 283.1; m/z found, 284.0 [M+H]⁺.¹H NMR (MeOD): 7.05-6.86 (m, 3H), 5.12-5.02 (m, 1H), 4.60-4.46 (m, 2H),4.32-4.20 (m, 3H), 4.09-4.00 (m, 1H), 3.95-3.87 (m, 2H), 3.86-3.70 (m,1H), 2.20-1.90 (m, 3H), 1.80-1.68 (m, 1H).

Example 167 3-[5-Chloro-2-(chroman-3-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1 [M+H]⁺.¹H NMR (MeOD): 7.15-6.63 (m, 7H), 5.15-4.98 (m, 1H), 4.60-3.90 (m, 8H),3.10-2.93 (m, 1H), 2.78-2.50 (m, 2H).

Example 168 3-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.1; m/z found, 334.1 [M+H]⁺.¹H NMR (CDCl₃): 7.45-7.25 (m, 5H), 7.04-6.88 (m, 3H), 5.05-4.96 (m, 1H),4.63-4.57 (m, 1H), 4.53-4.42 (m, 2H), 4.26-4.05 (m, 4H), 4.33 (s, 3H).

Example 1693-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈ClNO₃, 331.1; m/z found, 332.1 [M+H]⁺.¹H NMR (CDCl₃): 7.20-6.66 (m, 7H), 5.20-5.05 (m, 1H), 4.98-4.88 (m, 1H),4.35-4.03 (m, 6H), 3.42-3.32 (m, 1H), 3.12-3.03 (m, 1H).

Example 1705-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1,3-dimethyl-1H-pyrazole

MS (ESI): mass calcd. for C₁₅H₁₈ClN₃O₂, 307.1; m/z found, 308.1 [M+H]⁺.¹H NMR (MeOD): 7.12 (d, J=8.7 Hz, 1H), 7.00 (dd, J=8.7, 2.1 Hz, 1H),6.87 (d, J=2.1 Hz, 1H), 6.17 (s, 1H), 5.13-5.05 (m, 3H), 4.48-4.39 (m,2H), 4.18-4.12 (m, 2H), 3.85 (s, 3H), 2.20 (s, 3H).

Example 171 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found, 320.0 [M+H]⁺.¹H NMR (MeOD): 7.34-7.26 (m, 2H), 7.12-6.92 (m, 6H), 5.14-4.95 (m, 2H),4.83-4.74 (m, 1H), 4.48-4.42 (m, 1H), 4.39-4.30 (m, 4H), 4.24-4.16 (m,1H).

Example 1723-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-phenyl-azetidine

Prepared by the procedure of Example 163 using5-bromo-2-(3-fluoro-benzyloxy)-phenol and 1-phenyl-azetidin-3-ol. MS(ESI): mass calcd. for C₂₂H₁₉BrFNO₂, 427.1; m/z found, 428.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.34-6.47 (m, 12H), 5.11-5.03 (m, 3H), 4.36-4.28 (m, 2H),3.98-3.91 (m, 2H).

Example 173 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈ClNO₂, 315.1; m/z found, 316.1 [M+H]⁺.¹H NMR (MeOD): 7.35-7.06 (m, 6H), 6.93-6.90 (m, 1H), 5.28-5.21 (m, 1H),4.86-4.78 (m, 1H), 4.28-4.18 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m,2H), 3.18-3.08 (m, 2H).

Example 174 3-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈BrNO₂, 359.1; m/z found, 359.9 [M+H]⁺.¹H NMR (MeOD): 7.33-7.02 (m, 7H), 5.28-5.21 (m, 1H), 4.86-4.78 (m, 1H),4.28-4.16 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m, 2H), 3.18-3.08 (m,2H).

Example 175 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine

Step A: Preparation of 2-Bromo-5-fluoro-indan-1-one

To the solution of 5-fluoro-indan-1-one (10 mmol) in MeOH/CH₂Cl₂ (40mL/120 mL) was added Bu₄NBr₃ (11 mmol). The mixture was stirred at 25°C. for 16 h, concentrated and partitioned between CH₂Cl₂/H₂O (150 mL/80mL). The organic layer was concentrated and purified providing the titlecompound (2 g).

Step B: Preparation of3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5mmol), and K₂CO₃ (1 mmol) in acetonitrile (3 mL) was heated at 100° C.in a microwave reactor for 1 h. The mixture was cooled to rt andpurified via PTLC providing the title compound (150 mg). To this productwas added DCE (5 mL), Et₃SiH (1 mL) and TFA (3 mL). The mixture wasstirred at 80° C. for 16 h. After concentration, the title compound wasobtained (91 mg). MS (ESI): mass calcd. for C₁₈H₁₇ClFNO₂, 333.1; m/zfound, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.20-7.13 (m, 1H), 6.96-6.60 (m,5H), 5.18-5.08 (m, 1H), 4.93-4.83 (m, 1H), 3.98-3.70 (m, 4H), 3.38-3.05(m, 4H).

The compounds in Examples 176-178 were prepared according to Example 175using the appropriately substituted indanone.

Example 176 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇Cl₂NO₂, 349.1; m/z found, 350.0 [M+H]⁺.¹H NMR (CDCl₃): 7.26-6.63 (m, 6H), 5.20-5.05 (m, 1H), 4.93-4.83 (m, 1H),4.10-3.85 (M, 4H), 3.45-3.05 (m, 4H).

Example 177 3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.0 [M+H]⁺.¹H NMR (MeOD): 7.15 (d, J=8.2 Hz, 1H), 7.08-7.03 (m, 2H), 6.94-6.73 (m,3H), 5.25-5.17 (m, 1H), 4.90-4.81 (m, 1H), 4.80-4.70 (m, 2H), 4.12-4.02(m, 2H), 3.77 (s, 3H), 3.37-3.24 (m, 2H), 3.12-2.98 (m, 2H).

Example 178 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1 [M+H]⁺.¹H NMR (MeOD): 7.22-6.76 (m, 6H), 5.26-5.18 (m, 1H), 4.94-4.83 (m, 1H),4.18-4.10 (m, 2H), 3.98-3.88 (m, 2H), 3.83 (s, 3H), 3.40-3.20 (m, 2H),3.15-3.02 (m, 2H).

Example 179 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime

Step A: Preparation of3-[5-chloro-2-(6-fluoro-1-oxo-indan-2-yloxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (0.5 mmol), 1-bromo-indan-2-one (0.5 mmol), andK₂CO₃ (1 mmol) in actetonitrile (3 mL) was heated at 100° C. in amicrowave reactor for 1 h. The mixture was cooled down and separatedthrough PTLC providing the title compound (150 mg).

Step B: Preparation of3-[5-Chloro-2-(1-hydroxyimino-indan-2-yloxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

The title compound of Step A was dissolved into MeOH (2 mL), thenNH₂OH.HCl (1 mmol) and K₂CO₃ (2 mmol) were added. The mixture was heatedat 100° C. using a microwave reactor for 1 h. The mixture was cooled tort and purified by PTLC providing the title compound (120 mg).

Step C: Preparation of2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime

The title compound from Step B was dissolved in CH₂Cl₂ (20 mL), andCF₃COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h.After concentration and purification via PTLC, the title compound wasobtained (91 mg). MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₃, 344.1; m/zfound, 345.0 [M+H]⁺. ¹H NMR (MeOD): 8.40 (d, J=8.0 Hz, 1H), 7.50-6.80(m, 6H), 5.48-5.46 (m, 1H), 5.18-5.10 (m, 1H), 4.45-4.32 (m, 2H),4.18-4.08 (m, 2H), 3.62-3.52 (m, 1H), 3.16-3.08 (m, 1H).

Example 180-183 were prepared by the procedure of example 179 using theappropriate α-bromo-ketone and NH₂OH or NH₂OCH₃.

Example 180 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-oneO-methyl-oxime

MS (ESI): mass calcd. for C₁₉H₁₉ClN₂O₃, 358.1; m/z found, 359.0 [M+H]⁺.¹H NMR (MeOD): 8.70 (d, J=8.0 Hz, 1H), 7.60-6.90 (m, 6H), 6.03-5.98 (m,1H), 5.15-5.05 (m, 1H), 4.56-4.43 (m, 2H), 4.22-1.18 (m, 2H), 3.93 (s,3H), 3.76-3.64 (m, 1H), 3.24-3.16 (m, 1H).

Example 181 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanoneoxime

MS (ESI): mass calcd. for C₁₇H₁₇ClN₂O₃, 332.1; m/z found, 333.0 [M+H]⁺.¹H NMR (MeOD): 8.12-6.80 (m, 8H), 5.56-5.30 (m, 2H), 5.25-4.80 (m, 1H),4.60-3.98 (m, 4H).

Example 182 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanoneO-methyl-oxime

MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₃, 346.1; m/z found, 347.0 [M+H]⁺.¹H NMR (MeOD): 8.18-6.80 (m, 8H), 5.56-5.33 (m, 2H), 5.32-4.80 (m, 1H),4.60-3.98 (m, 7H).

Example 1832-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-(4-chloro-phenyl)-ethanone

¹H NMR (CDCl₃): 7.97 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.85(dd, J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H),5.25 (s, 2H), 5.00-4.97 (m, 1H), 3.98-3.80 (m, 4H).

Example 1843-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (0.5 mmol), (2-bromo-1,1-difluoro-ethyl)-benzene(1 mmol), and K₂CO₃ (1 mmol) in acetonitrile (3 mL) was heated at 180°C. in a microwave reactor for 1 h. The mixture was cooled to rt andpurified via PTLC providing3-[5-chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester (90 mg). To this compound was added CH₂Cl₂ (20 mL)and CF₃COOH (3 mL). The mixture was stirred at rt for 4 h andconcentrated to give the title compound (50 mg). MS (ESI): mass calcd.for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.0 [M+H]⁺. ¹H NMR (MeOD):7.66-7.46 (m, 5H), 7.02-6.83 (m, 3H), 5.05-4.95 (m, 1H), 4.50 (t, J=12.7Hz, 2H), 4.30-4.20 (m, 2H), 4.10-3.98 (m, 2H).

Example 1853-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

Step A. Preparation of Methanesulfonic acid 2-(3-chloro-phenyl)-ethylester

To a solution of 2-(3-chloro-phenyl)-ethanol (566 mg, 3.6 mmol) inCH₂Cl₂ (10 mL) was added methanesulfonyl chloride (310 μL, 4.0 mmol).After 5 min, Et₃N (756 μL, 5.4 mmol) was added and the reaction wasallowed to stir for 18 h. The reaction was then diluted with H₂O. Theorganic layer was separated and washed with H₂O, brine, then dried andconcentrated to give a yellow oil (770 mg, 91%). ¹H NMR (CDCl₃):7.27-7.23 (m, 3H), 7.14-7.11 (m, 1H), 4.41 (t, J=6.8 Hz, 2H), 3.04 (t,J=6.8 Hz, 2H), 2.90 (s, 3H).

Step B. Preparation of3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To a solution of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (60 mg, 0.20 mmol) in DMF (2 mL) was added NaH (10mg, 0.24 mmol). After 5 min, the title compound of Step A (56 mg, 0.24mmol) was added and the resulting mixture was heated at 65° C. for 18 h.The reaction was diluted with H₂O and extracted EtOAc (3×). The organicswere dried and purified by RP HPLC (Agilent) to give the title compoundas an oil (47 mg, 54%). MS (ESI): mass calcd. for C₂₂H₂₅Cl₂NO₄, 438.3;m/z found, 382.0 [M−56+H]⁺. ¹H NMR (CDCl₃): 7.34-7.32 (m, 1H), 7.25-7.22(m, 2H), 7.19-7.16 (m, 1H), 6.90 (dd, J=8.8, 2.0 Hz, 1H), 6.78 (d, J=8.8Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.30-4.25 (m, 2H),4.16 (t, J=6.7 Hz, 2H), 4.07-4.03 (m, 2H), 3.10 (t, J=6.7 Hz, 2H), 1.46(s, 9H).

Step C: Preparation of3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared from title compound of Step B using general procedure 1. MS(ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 338.2; m/z found, 338.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.35-7.34 (m, 1H), 7.25-7.21 (m, 3H), 7.18-7.16 (m, 1H),6.88-6.85 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H),4.98-4.91 (m, 1H), 4.17 (t, J=6.8 Hz, 2H), 3.96-3.85 (m, 4H), 3.10 (t,J=6.7 Hz, 2H).

The compounds in Examples 186-195 were synthesized according to Example185 using the appropriately substituted mesylates as prepared in Example185 Step A.

Example 186 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.8; m/z found, 304.1 [M+H]⁺.¹H NMR (CDCl₃): 7.39-7.19 (m, 7H), 6.93-6.73 (m, 2H), 6.58 (d, J=2.4 Hz,1H), 4.94 (s, 1H), 4.18 (t, J=7.3 Hz, 2H), 3.91 (s, 3H), 3.14 (t, J=7.3Hz, 2H).

Example 187 3-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.1 [M+H]⁺.¹H NMR (CDCl₃): 7.42 (s, 5H), 6.87-6.61 (m, 2H), 6.62 (d, J=2.2 Hz, 1H),5.85 (dd, J=48.0, 8.0 Hz, 1H), 5.02 (bs, 1H), 4.40-4.08 (m, 7H).

Example 1883-[5-Chloro-2-[1-(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂NO₂, 378.3; m/z found, 378.0 [M+H]⁺.¹H NMR (CDCl₃): 7.34-7.27 (m, 5H), 7.21-7.20 (m, 1H), 7.19-7.18 (m 1H),6.81 (s, 1H), 6.70 (d, J=8.6, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.97-4.87 (m,1H), 4.01 (s, 2H), 3.94-3.90 (m, 2H), 3.82-3.78 (m, 2H), 2.42 (t, J=7.7Hz, 4H).

Example 1893-[5-Chloro-2-[1-(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂NO₂, 378.3; m/z found, 378.0. ¹H NMR(CDCl₃): 7.28-7.22 (m, 5H), 7.19-7.16 (m, 1H), 7.13-7.10 (m, 1H), 6.82(dd, J=8.6, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.4, 1 H),4.92 (m, 1H), 4.03 (s, 2H), 3.94-3.76 (m, 3H), 2.42 (d, J=8.8 Hz, 3H),2.17 (s, 2H).

Example 1903-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.8; m/z found, 334.1 [M+H]⁺.¹H NMR (CDCl₃): 7.24-7.22 (m, 2H), 6.90-6.86 (m, 3H), 6.81-6.77 (m, 2H),6.60 (d, J=2.4, 1 H), 5.00-4.87 (m, 1H), 4.18 (t, J=7.2, 2H), 4.03-3.94(m, 2H), 3.90-3.86 (m, 2H), 3.80 (s, 3H), 3.11 (t, J=7.1 Hz, 2H).

Example 1913-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.0 [M+H]⁺.¹H NMR (CDCl₃): 7.30-7.24 (m, 2H), 7.09-7.05 (m, 2H), 6.96-6.91 (m, 1H),6.88-6.85 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4, 1 H), 4.95(s, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.95-3.84 (m, 4H), 3.12 (t, J=6.8 Hz,2H).

Example 1923-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 338.2; m/z found, 338.0. ¹H NMR(CDCl₃): 7.34-7.17 (m, 5H), 6.89 (dd, J=8.6, 2.4 Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.95 (t, J=6.2 Hz, 1H), 4.16-4.13 (m,2H), 4.04-3.99 (m, 2H), 3.93-3.89 (m, 2H), 3.09 (t, J=6.9 Hz, 2H).

Example 1933-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.1 [M+H]⁺.¹H NMR (CDCl₃): 7.32-7.20 (m, 4H), 7.00 (t, J=8.7 Hz, 1H), 6.87-6.85 (m,1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 5.00-4.87 (m, 1H),4.15 (t, J=7.0 Hz, 2H), 3.94-3.90 (m, 2H), 3.85-3.81 (m, 2H), 3.10 (t,J=7.0 Hz, 2H).

Example 1943-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.8; m/z found, 334.1 [M+H]⁺.¹H NMR (CDCl₃): 7.22-7.20 (m, 2H), 6.93-6.85 (m, 3H), 6.77 (d, J=8.4 Hz,1H), 6.58 (d, J=2.4 Hz, 1H), 4.98-4.91 (m, 1H), 4.13 (t, J=7.3 Hz, 2H),3.96-3.92 (m, 2H), 3.89-3.85 (m, 2H), 3.79 (s, 3H), 3.07 (t, J=7.3 Hz,2H).

Example 195 3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine

Prepared according to Example 185 using3-(5-Bromo-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester. MS (ESI): mass calcd. for C₁₇H₁₈BrNO₂, 348.2; m/z found, 348.0.¹H NMR (CDCl₃): 7.39-7.20 (m, 6H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.76(dd, J=6.8, 5.5 Hz, 2H), 4.99-4.87 (m, 1H), 4.18 (t, J=7.2 Hz, 2H),4.03-3.98 (m, 2H), 3.95-3.91 (m, 2H), 3.13 (t, J=7.2 Hz, 2H).

Example 196 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine

Step A: Preparation of 2-benzyloxy-5-chloro-3-fluoro-pyridine

To 60% NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 mL) was addedbenzyl alcohol (2.7 g, 2.6 mL, 25.0 mmol) dropwise. After 1 h,5-chloro-2,3-difluoro-pyridine (3.73 g, 25.0 mmol) was added in THF (5mL). After an additional 18 h, H₂O was added and the mixture extractedwith EtOAc (2×). The combined organics were washed with brine and dried.Silica gel chromatography (1-15% EtOAc in hexanes) gave 4.02 g (67%yield) of the title compound as a clear oil. ¹H NMR (CDCl₃): 7.91 (d,J=2.2 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).

Step B: Preparation of3-(2-Benzyloxy-5-chloro-pyridin-3-yloxy)-azetidine-1-carboxylic acidtert-butyl ester

To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.35 g, 2.0mmol) in NMP (3 mL) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol).After 20 min at rt, the reaction was heated to 50° C. for 20 min, cooledto rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1mL) was added. The reaction was then heated in a microwave reactor at145° C. for 1 h, cooled to rt, poured into H₂O and extracted with EtOAc(2×). The combined organics were washed with brine and dried.

Silica gel chromatography (2-15% EtOAc in hexanes) gave 0.34 g (51%yield) of the title compound as a white solid. ¹H NMR (CDCl₃): 7.74 (d,J=2.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 2H), 7.39-7.30 (m, 3H), 6.77 (d, J=2.1Hz, 1H), 5.42 (s, 2H), 4.87-4.82 (m, 1H), 4.26 (dd, J=10.5, 6.4 Hz, 2H),4.05 (dd, J=10.3, 4.2 Hz, 2H), 1.44 (s, 9H).

Step C: Preparation of3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine

Prepared from the title compound of Step B using general procedure 1. MS(ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]. ¹HNMR (CDCl₃): 7.70 (d, J=2.2 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.37 (t,J=7.2 Hz, 2H), 7.33-7.29 (m, 1H), 6.77 (d, J=2.2 Hz, 1H), 5.43 (s, 2H),4.99-4.93 (m, 1H), 3.96-3.81 (m, 4H).

Example 197 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine

Step A: Preparation of 4-Chloro-2,6-difluoro-benzaldehyde

To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol)in THF (70 mL) at was added n-butyl lithium (1.6 M in hexane, 19 mL).After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction wasallowed to warm to rt over 18 h. After the addition of 0.5 M HCl (150mL) and ether (150 mL), the aqueous layer was extracted with Et₂O (3×).The combined organic extracts were dried and concentrated to provide ayellow solid. The crude material was dissolved in warm hexanes and asmall amount of white solid formed upon cooling. This white solid wasfiltered off and discarded. The filtrate was concentrated to provide thetitle compound as a light yellow solid (2.5 g, 41%). ¹H NMR (CDCl₃):10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).

Step B: Preparation of3-(5-Chloro-3-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

To a solution of the title compound of Step A (270 mg, 1.5 mmol) and3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (270 mg, 1.5mmol) in dry DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 22mg, 1.5 mmol). After 18 h, H₂O and EtOAc were added and the aqueouslayer was extracted with EtOAc. The combined organic extracts were driedand concentrated. The crude residue was purified by RP HPLC to providethe title compound (75 mg, 15%). MS (ESI): mass calcd. for C₁₅H₁₇ClFNO₄,329.1; m/z found, 274.0 [M+H−56]⁺. ¹H NMR (CDCl₃): 10.4 (s, 1H), 6.84(dd, J=10.0, 1.6 Hz, 1H), 6.39 (dd, J=1.4, 1.3 Hz, 1H), 5.00-4.92 (m,1H), 4.38 (dd, J=9.9, 6.3 Hz, 2H), 4.08 (dd, J=10.7, 4.0 Hz, 2H), 1.46(s, 9H).

Step C: Preparation of3-(5-Chloro-3-fluoro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

To a solution of the title compound of Step B (650 mg, 2.0 mmol) inCH₂Cl₂ (100 mL) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirringfor 72 h, the starting aldehyde remained as determined by analyticalHPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol)was added. After 18 h, analytical HPLC analysis indicated that thereaction was complete. A solution of 10% aqueous sodium bisulfite (100mL) was added to the reaction mixture. After an additional 18 h, CH₂Cl₂was added and the aqueous portion extracted three times with CH₂Cl₂. Thecombined organic extracts were washed with saturated NaHCO₃ (2×) andconcentrated. The residue was then treated with MeOH (500 mL) and 1 NNaOH (250 mL). The solution immediately turned dark brown. After 2 h,the MeOH was removed by rotary evaporation and 1 M KHSO₄ was added tothe residue until the pH of the solution reached pH=4. The reactionmixture was then extracted with EtOAc (3×). The combined organic layerswere washed with brine and dried. The residue was purified by RP HPLC toprovide the desired phenol (290 mg, 46%). ¹H NMR (CDCl₃): 6.74 (dd,J=10.1, 2.3 Hz, 1H), 6.30 (dd, J=2.0, 2.1 Hz, 1H), 4.87-4.80 (m, 1H),4.26 (dd, J=9.9, 6.4 Hz, 2H), 4.00 (dd, J=9.9, 3.8 Hz, 2H), 3.29-3.13(m, 1H), 1.40 (s, 9H).

Step D: Preparation of3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

Prepared from the title compound of Step C using according to Example 1Step D. MS (ESI): mass calcd. for C₂₁H₂₃ClFNO₄, 407.1; m/z found, 430.0[M+Na]⁺. ¹H NMR (CDCl₃): 7.46-7.29 (m, 5H), 6.79 (dd, J=9.9, 2.4 Hz,1H), 6.29 (dd, J=2.1, 2.1 Hz, 1H), 5.06 (s, 2H), 4.82-4.72 (m, 1H), 4.25(ddd, J=9.7, 6.4, 1.0 Hz, 2H), 3.92 (dd, J=9.8, 3.9 Hz, 2H), 1.46 (s,9H).

Step E: Preparation of3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine

Prepared from the title compound of Step D using general procedure 1. MS(ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.0 [M+H]⁺. ¹HNMR (CDCl₃): 7.47-7.41 (m, 2H), 7.37-7.30 (m, 3H), 6.76 (dd, J=9.9, 2.4Hz, 1H), 6.34 (dd, J=2.1, 2.1 Hz, 1H), 5.06 (s, 2H), 4.97-4.86 (m, 1H),4.05-3.63 (m, 4H), 2.27-2.00 (m, 1H).

Example 1983-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according to Example 199 using2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. forC₁₅H₁₂ClF₄NO₃, 365.0; m/z found, 367.0 [M+H]⁺. ¹H NMR (CDC₃): 6.78-6.72(m, 2H), 6.42 (d, J=3.3 Hz, 1H), 6.36 (dd, J=2.1, 2.1 Hz, 1H), 5.04 (s,2H), 4.98-4.85 (m, 1H), 4.05-3.69 (m, 4H), 2.20-1.99 (m, 1H).

Example 1993-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according to Example 1 using3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester and 2-bromomethyl-5-trifluoromethyl-furan. MS (ESI):mass calcd. for C₁₆H₁₃F₆N₃O₃, 381.1; m/z found, 382.0 [M+H]⁺. ¹H NMR(CDCl₃): 7.21 (dd, J=8.4, 1.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (d,J=2.0 Hz, 1H), 6.79-6.78 (m, 1H), 6.51 (d, J=3.1 Hz, 1H), 5.13 (s, 2H),5.05-4.99 (m, 1H), 3.94-3.87 (m, 4H).

Example 2003-[5-Trifluoromethyl-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared according to Example 101 using3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester. MS (ESI): mass calcd. for C₁₉H₁₇F₆NO₂, 405.1; m/zfound, 406.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (s, 1H), 7.56 (t, J=7.6 Hz,2H), 7.47 (t, J=7.7 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.83-6.80 (m, 2H),5.41 (q, J=6.4 Hz, 1H), 5.07 (br s, 1H), 4.33-3.64 (m, 4H), 1.70 (d,J=6.5 Hz, 3H).

Example 201 3-[2-(1-Phenyl-ethoxy)-5-trifluoromethyl-phenoxy]-azetidinehydrochloride

Prepared according to Example 1 using3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester and benzyl bromide. MS (ESI): mass calcd. forC₁₇H₁₆F₃NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.39 (s,2H), 7.49-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.13(d, J=1.9 Hz, 1H), 5.23 (s, 2H), 5.14-5.10 (m, 1H), 4.39-4.34 (m, 2H),4.01-3.98 (m, 2H).

Example 202 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidinehydrochloride

Step A: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-benzaldehyde

A mixture of 5-fluorosalicyladehyde (5.0 g, 36 mmol), 3-chloro-benzylbromide (7.34 g, 35.7 mmol), K₂CO₃ (6.0 g, 43 mmol) in DMF (50 mL) washeated at 65° C. for 18 h. The reaction mixture was cooled to rt anddiluted with a mixture of EtOAc (500 mL) and H₂O (300 mL). The organicphase was separated, washed with H₂O (3×250 mL), and dried to give thetitle compound (9.4 g, 99%) that was used without further purification.

Step B: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-phenol

To the title compound from Step A (9.4 g, 36 mmol) in CH₂Cl₂ (200 mL)was added 77% m-CPBA (12.0 g, 54.0 mmol). The mixture was allowed tostir for 36 h at rt and 10 wt % NaHSO₃ (aq.) solution was added. After48 h, the reaction mixture was washed with H₂O (2×250 mL). The organiclayer was dried and treated with 1N NaOH (100 mL) and MeOH (100 mL).After 48 h, the MeOH was removed and 1N H₂SO₄ was added slowly to adjustthe pH to 1.5. The resulting solution was extracted with CH₂Cl₂ (3×150mL). The combined extracts were washed with H₂O and dried to give a redoil (8.4 g). Chromatography (SiO₂. 0-20% EtOAc/hexane) gave the titlecompound (5.0 g, 56%). ¹H NMR (CDCl₃) 7.50-7.16 (m, 4H), 6.87-6.57 (m,2H), 6.50 (t, J=8.6, 3.0 Hz, 1H), 5.80 (s, 1H), 5.05-4.89 (m, 2H).

Step C: Preparation of3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine-1-carboxylic acidtert-butyl ester

To the title compound of Step B (200 mg, 0.79 mmol) in DMF (5.0 mL) wasadded 60 wt % NaH (34.3 mg, 0.86 mmol). The mixture was heated to 50° C.for 1 h then cooled to rt and3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester(Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added. This mixturewas heated to 80° C. for 18 h, cooled to rt and treated with EtOAc (50mL) and H₂O (100 mL). The organic layer was separated, washed with H₂O(2×50 mL) and dried to give a solid (400 mg). This solid was purified onRP HPLC to yield the title compound (90 mg, 28%). ¹H NMR (CDCl₃) 7.44(s, 1H), 7.36-7.23 (m, 3H), 6.86 (dd, J=8.9, 5.4 Hz, 1H), 6.60 (dd,J=8.0, 2.9 Hz, 1H), 6.33 (dd, J=9.6, 2.9 Hz, 1H), 5.03 (s, 2H),4.90-4.80 (m, 1H), 4.33-4.22 (m, 2H), 4.07-4.02 (m, 2H), 1.54-1.28 (m,9H).

Step D: Preparation of3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine hydrochloride

The title compound from step C (85 mg) was dissolved in MeOH (5 mL) and4M HCl in dioxane (3 mL) was added. The mixture was stirred at rt for 18h. The reaction was concentrated and dried under vacuum to yield thetitle compound (75 mg). MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.8;m/z found, 310.2 [M+H]⁺. ¹H NMR (MeOD): 7.46 (s, 1H), 7.37-7.28 (m, 3H),7.04 (dd, J=9.0 Hz, 5.3, 1H), 6.75-6.61 (m, 2H), 5.09-5.00 (m, 3H), 4.42(dd, J=12.7, 6.6 Hz, 2H), 4.14 (dd, J=12.7, 4.9 Hz, 2H).

Example 2033-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-methyl-azetidine

Prepared according to general procedure 5 using the title compound fromExample 202. MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found,322.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.39 (m, 1H), 7.31-7.25 (m, 3H), 6.81(dd, J=8.9, 5.5 Hz, 1H), 6.56-6.52 (m, 1H), 6.38 (dd, J=9.9, 2.9 Hz,1H), 5.02 (s, 2H), 4.72-4.67 (m, 1H), 3.87-3.78 (m, 2H), 3.17-3.08 (m,2H), 2.40 (s, 3H).

Example 2043-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-isopropyl-azetidine

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 202. MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.8; m/zfound, 350.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.29-7.26 (m, 3H),6.81 (dd, J=8.9, 5.5 Hz, 1H), 6.54-6.52 (m, 1H), 6.41 (dd, J=9.9, 2.9, 1H), 5.01 (s, 2H), 4.73-4.68 (m, 1H), 3.85-3.77 (m, 2H), 3.11-3.04 (m,2H), 2.43-2.36 (m, 1H), 0.95 (d, J=6.2 Hz, 6H).

Example 2053-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-cyclobutyl-azetidine

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 202. MS (ESI): mass calcd. for C₂₀H₂₁ClFNO₂, 361.8; m/zfound, 362.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.32-7.22 (m, 3H),6.82 (dd, J=8.9, 5.5 Hz, 1H), 6.57-6.53 (m, 1H), 6.41 (dd, J=9.8, 2.9Hz, 1H), 5.02 (s, 2H), 4.77-4.72 (m, 1H), 3.77-3.69 (m, 2H), 3.23-3.12(m, 3H), 2.01-1.95 (m, 2H), 1.87-1.62 (m, 4H).

Example 2063-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-propyl-azetidine

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 202. MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.8; m/zfound, 350.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (s, 1H), 7.30 (m, 3H), 6.83(dd, J=8.9, 5.5 Hz, 1H), 6.59-6.51 (m, 1H), 6.42 (dd, J=9.9, 2.9 Hz,1H), 5.04 (s, 2H), 4.78-4.73 (m, 1H), 3.8-3.80 (m, 2H), 3.13-3.05 (m,2H), 2.52-2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).

Example 2073-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-ethyl-azetidine

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 202. MS (ESI) mass calcd. for C₁₈H₁₉ClFNO₂, 335.8; m/zfound, 338.2 [M+H]⁺. ¹H NMR (CDCl₃) 7.47 (s, 1H), 7.32-7.28 (m, 3H),6.84 (dd, J=8.9, 5.5 Hz, 1H), 6.59-6.55 (m, 1H), 6.43 (dd, J=9.8, 2.9Hz, 1H), 5.04 (s, 2H), 4.79-4.74 (m, 1H), 3.87-3.80 (m, 2H), 3.15-3.06(m, 2H), 2.59-2.54 (m, 2H), 1.01 (dd, J=8.8, 5.6 Hz, 3H).

Example 2083-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according top Example 202 using2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. forC₁₅H₁₃F₄NO₃, 331.26; m/z found, 332.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.91 (dd,J=8.9, 5.5 Hz, 1H), 6.77 (d, J=2.3, 1 H), 6.66-6.53 (m, 1H), 6.49-6.29(m, 2H), 5.04 (s, 2H), 5.00-4.92 (m, 1H), 3.98-3.94 (m, 4H), 2.44 (s br,1H).

Example 2093-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-1-isopropyl-azetidine

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 208. MS (ESI): mass calcd. for C₁₈H₁₉F₄NO₃, 373.3; m/zfound, 374.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.89 (dd, J=8.9, 5.5 Hz, 1H),6.77-6.75 (m, 1H), 6.63-6.51 (m, 1H), 6.44-6.41 (m, 2H), 5.01 (s, 2H),4.78-4.58 (m, 1H), 3.83 (dd, J=8.8, 6.0 Hz, 2H), 3.09 (dd, J=8.8, 6.0Hz, 2H), 2.47-2.31 (m, 1H), 0.97 (d, J=6.2 Hz, 6H).

Example 210 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine

3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1-carboxylic acidtert-butyl ester (188 mg, 0.4 mmol), 3-thiophene boronic acid (53 mg,0.41 mmol), Q-Phos (23 mg, 0.032 mmol), Pd(dba)₂ (9.2 mg, 0.016 mmol)and K₃PO₄ (255 mg, 1.2 mmol) were taken into toluene (3 mL) and heatedat 80° C. After the reaction was complete it was cooled to rt, dilutedwith CH₂Cl₂ (20 mL), filtered, washed with H₂O (2×25 mL) and concentratdto give3-[2-(3-chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester. To this compound was added MeOH (10 mL) followedby 4M HCl in dioxane (4 mL). After 4 h the reaction was concentrated andpurified on RP HPLC (basic) to yield the title compound (12 mg). MS(ESI): mass calcd. for C₂₀H₁₈ClNO₂S, 371.9; m/z found, 372.2 [M+H]⁺. ¹HNMR (CDCl₃): 10.30-9.57 (m, 1H), 7.43 (s, 1H), 7.40-7.28 (m, 6H), 7.24(dd, J=8.4, 2.1 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H),5.24-4.99 (m, 3H), 4.40-4.11 (m, 4H).

Example 2113-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzamide

A suspension of3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1-carboxylic acidtert-butyl ester (94 mg, 0.2 mmol), Na₂CO₃ (53 mg, 0.5 mmol), 40% Me₂NHin H₂O (0.17 mmol), Hermann's catalyst (8 mg, 0.008 mmol) and Mo(CO)₆(22 mg, 0.083 mmol) in H₂O (2 mL) was heated to 170° C. in a microwavereactor for 10 min. The reaction was cooled rt, and saturated NaHCO₃(aq.) was added. This solution was extracted with CH₂Cl₂ (3×). Thecombined organic layers were concentrated to give a solid (30 mg) thatwas dissolved in MeOH (2 mL) and treated with 4M HCl in dioxane (1 mL).After 3 h, the mixture was concentrated to give a residue that waspurified on RP HPLC providing the title compound (5 mg). MS (ESI): masscalcd. for C₁₉H₂₁ClN₂O₃, 360.8; m/z found, 361.5 [M+H]⁺. ¹H NMR (CDCl₃):7.45 (s, 1H), 7.29-7.27 (m, 3H), 6.96 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d,J=8.3 Hz, 1H), 6.72 (d, J=1.9 Hz, 1H), 5.11 (s, 2H), 5.05-4.95 (m, 1H),3.92-3.85 (m, 4H), 3.00 (s br, 6H).

Example 2123-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

Step A: Preparation of 1-benzhydryl-3-methyl-azetidin-3-ol

To 1-benzhydryl-azetidin-3-one (1.0 g, 4.2 mmol) in ether (100 mL) at 0°C. was added CH₃MgBr (1.5 mL, 3M in ether). The mixture was warmed to rtover 1 h and 1N NaOH (3 mL) was added. The organic layer wasconcentrated providing the title compound (1.1 g). MS (ESI): mass calcd.for C₁₇H₁₉NO, 253.2; m/z found, 254.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.42-7.11(m, 10H), 4.32 (s, 1H), 3.14 (d, J=8.5 Hz, 2H), 2.96 (d, J=8.5 Hz, 2H),1.43 (s, 3H).

Step B: Preparation of1-benzhydryl-3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

The mixture of the title compound from Step A (0.5 mmol),5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), andcyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) washeated at 150° C. in a microwave reactor for 1 h. The mixture was cooledto rt and purified via PTLC providing the title compound (120 mg). MS(ESI): mass calcd. for C₃₀H₂₇BrClNO₂, 547.1; m/z found, 548.0 [M+H].

Step C: Preparation of3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

The title compound from Step B (60 mg) was dissolved in DCE (10 mL) andchloroethylformate (0.2 mmol) was added. The mixture was heated at80-100° C. for 1 h and concentrated. The residue was dissolved in MeOH(3 mL) and heated at 150° C. in a microwave reactor for another 1 h. Themixture was cooled to rt and purified via PTLC providing the titlecompound (30 mg). MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/zfound, 382.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.23 (m, 4H), 7.12-7.06 (m,1H), 6.86-6.78 (m, 2H), 5.12 (s, 2H), 4.24-4.16 (m, 2H), 3.78-3.67 (m,2H), 1.67 (s, 3H).

Example 213 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine

Prepared according to Example 212 using the ethylmagnesium bromide inStep A. MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1[M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.25 (m, 4H), 7.15-7.05 (m, 1H), 6.84-6.73(m, 2H), 5.13 (s, 2H), 4.26-4.19 (m, 2H), 3.85-3.74 (m, 2H), 2.19-2.00(m, 2H), 1.00-0.90 (m, 3H).

Example 2143-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine

Prepared according to Example 212 using the isopropylmagnesium bromidein Step A. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 409.0; m/z found,409.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.23 (m, 4H), 7.14-6.78 (m, 3H), 5.13(s, 2H), 3.98-3.85 (m, 2H), 3.48-3.33 (m, 2H), 1.45-1.36 (m, 1H),0.63-0.50 (m, 6H).

Example 215 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine

Step A: Preparation of (4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine

A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 47 mmol), tert-butylamine (6.1 mL, 57 mmol) and 4 Å powder molecular sieves (8.0 g) in 160mL CH₂Cl₂ (160 mL) was stirred at rt for 18 h. The reaction mixture wasfiltered through a pad of celite and concentrated to give the titlecompound (9.9 g, 78%). MS (ESI): mass calcd. for C₁₁H₁₃BrFNO, 258.1; m/zfound, 260.0 [M+H]⁺. ¹H NMR (CDCl₃): 10.32 (s, 1H), 8.48 (s, 1H), 7.89(t, J=8.1 Hz, 1H), 7.50-7.20 (m, 1H), 1.49-1.08 (m, 9H).

Step B: Preparation of 3-hydroxy-3-methyl-azetidine-1-carboxylic acidtert-butyl ester

A solution of 1-Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 mL anh Et₂Owas cooled to 0° C. and 3M MeMgBr in Et₂O (10 mL, 30 mmol) was addeddropwise over 1 h. After 45 min, the reaction was allowed to warm to rtand stir an additional for 18 h. Then 1 sat'd NH₄Cl (aq.) was added andthe mixture extracted with EtOAc (2×). The combined organic layers weredried and the resulting semisolid was purified by RP HPLC (Agilent) togive the title compound as a white solid (3.2 g, 84%). ¹H NMR (CDCl₃):3.84 (q, J=9.2 Hz, 4H), 1.97 (bs, 1H), 1.52 (s, 3H), 1.44 (m, 9H).

Step C: Preparation of3-(5-Bromo-2-formyl-phenoxy)-3-methyl-azetidine-1-carboxylic acidtert-butyl ester

To a solution of the title compound from Step B (400 mg, 2.2 mmol) inDMSO (8 mL) was added 60% NaH (120 mg, 3.0 mmol). After 30 min, thetitle compound from Step A was added and the resulting mixture washeated at 125° C. for 1 h in a microwave reactor. An additional quantityof the title compound from Step B (100 mg) and 60% NaH (32 mg) wereadded to the reaction. Heating was then resumed at 125° C. for another 1h in a microwave reactor. The reaction was diluted with H₂O andextracted with EtOAc (3×) followed by methanolic EtOAc (2×). Theorganics were dried, then THF (5 mL), H₂O (5 mL) and AcOH (3 mL) wereadded. After 18 h at rt, the reaction was diluted with H₂O and extractedwith CH₂Cl₂. The organics were dried and purified by PTLC to give thetitle compound as an off white solid (247 mg, 31%). ¹H NMR (CDCl₃):10.36 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.22-7.20 (m, 1H), 6.68 (d, J=1.6Hz, 1H), 4.25 (d, J=9.2 Hz, 2H), 4.03 (d, J=9.8 Hz, 2H), 1.55 (s, 3H),1.46 (m, 9H).

Step D: Preparation of3-(5-Bromo-2-hydroxy-phenoxy)-3-methyl-azetidine-1-carboxylic acidtert-butyl ester

Prepared according to Example 1 Step C using the title compound fromStep C. Purification was accomplished by PTLC to give the title compoundas a peach solid (152 mg, 64%). ¹H NMR (CDCl₃): 7.02 (dd, J=8.5, 2.2 Hz,1H), 6.84 (d, J=8.5 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 4.22 (d, J=9.2 Hz,2H), 3.98 (d, J=9.5 Hz, 2H), 3.49 (s, 1H), 1.69 (s, 3H), 1.46 (s, 9H).

Step E. Preparation of3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acidtert-butyl ester

A mixture of3-(5-bromo-2-hydroxy-phenoxy)-3-methyl-azetidine-1-carboxylic acidtert-butyl ester (30 mg. 0.08 mmol), (2-bromoethyl)benzene (29 μL, 0.21mmol), KI (42 mg, 0.25 mmol) and Cs₂CO₃ (82 mg, 0.25 mmol) in 3 mL DMFwas stirred at rt for 18 h. The reaction mixture was diluted with H₂Oand extracted with EtOAc (3×). The organic layers were dried andpurified by RP HPLC (Agilent) to give the title compound as an oil (22mg, 58%). MS (ESI): mass calcd. for C₂₃H₂₈BrNO₄, 462.4; m/z found, 408.0[M−56+H]⁺. ¹H NMR (CDCl₃): 7.38-7.18 (m, 5H), 7.07 (dd, J=8.6, 2.3 Hz,1H), 6.76-6.74 (m, 2H), 4.24-4.08 (m, 4H), 3.84 (d, J=9.7 Hz, 2H), 3.11(t, J=7.1 Hz, 2H), 1.58 (s, 3H), 1.45 (s, 9H).

Step F: Preparation of3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine

A mixture of3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acidtert-butyl ester (20 mg) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred atrt for 2 h. The reaction was concentrated in vacuo and purified by PTLCfollowed by additional purification using RP HPLC (Agilent) to give thetitle compound as an oil (12 mg, 77%). MS (ESI): mass calcd. forC₁₈H₂₀BrNO₂, 362.3; m/z found, 362.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.18(m, 5H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (dd, J=5.5, 3.1, 2H), 4.15(t, J=7.2 Hz, 2H), 3.97 (d, J=8.9 Hz, 2H), 3.45 (d, J=9.2 Hz, 2H), 3.11(t, J=7.1 Hz, 2H), 1.98 (s, 1H), 1.65 (s, 3H).

The compounds in Examples 216-217 were prepared according to Example 215using the appropriate alkyl halide in Step E.

Example 2163-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrF₃NO₃, 406.2; m/z found, 407.9 [M+H]⁺.¹H NMR (CDCl₃): 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H),6.76-6.75 (m, 2H), 6.45-6.44 (m, 1H), 5.02 (s, 2H), 4.00 (d, J=9.0 Hz,2H), 3.59-3.43 (m, 2H), 2.35 (br s, 1H), 1.67 (s, 3H).

Example 2173-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 416.2; m/z found, 416.0 [M+H]⁺.¹H NMR (CDCl₃): 7.72 (bs, 1H), 7.59-7.57 (m, 2H), 7.51-7.46 (m, 2H),7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.4 Hz,1H), 5.11 (s, 2H), 4.03 (br s, 2H), 3.54 (bs, 2H), 1.71 (s, 3H).

Example 218 3-(5-Bromo-2-phenoxy-phenoxy)-3-methyl-azetidine

Prepared according to general procedure 6 using the title compound ofExample 215 Step D. MS (ESI): mass calcd. for C₁₆H₁₆BrNO₂, 334.2; m/zfound, 334.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.24 (m, 2H), 7.08-7.04 (m,2H), 6.94-6.86 (m, 3H), 6.80 (d, J=2.3, 1 H), 3.88 (d, J=8.3 Hz, 2H),3.46 (d, J=8.7 Hz, 2H), 1.85 (br s, 1H), 1.65 (s, 3H).

Example 219(±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Step A. Preparation of (±)-2-bromomethyl-3-methyl-oxirane

See Shimizu et al., Organic Process & Research Development, 2005, Vol9(3), pp. 278-287. To a stirred solution of crotyl bromide (10 g, 63mmol) in CH₂Cl₂ (200 mL) was slowly added 77% m-CPBA (19.8 g, 88 mmol)portionwise over 45 min. After stirring at rt for 18 h, the solids wereremoved by filtration. The filtrate was treated with aqueous 10% aq.NaHSO₃ (150 mL) and stirred at rt for 5 h. The organic layer wasseparated, washed with sat'd NaHCO₃ (3×), brine (2×) and dried to givethe title compound as a colorless oil (6.6 g, 70%). ¹H NMR (CDCl₃):3.43-3.39 (m, 1H), 3.35-3.18 (m, 1H), 3.04-2.89 (m, 2H), 1.35 (d, J=5.2Hz, 3H).

Step B. Preparation of cis and trans 1-benzhydryl-2-methyl-azetidin-3-ol

See PCT pat appl. WO 01/01988. A mixture of2-bromomethyl-3-methyl-oxirane (3.6 g, 23.8 mmol) andaminodiphenylmethane (4.1 mL, 23.8 mmol) in 12 mL MeOH was stirred at rtfor 72 h. Next, the reaction was heated at reflux for 72 h. Aftercooling to rt, the reaction was purified by reverse phase basic HPLC(Agilent) to give the cis and trans isomers of the title compound. Transisomer as an oil (424 mg), ¹H NMR (CDCl₃): 7.44-7.35 (m, 4H), 7.28-7.12(m, 7H), 4.34 (s, 1H), 3.93-3.90 (m, 1H), 3.67-3.64 (m, 1H), 3.03-2.99(m, 1H), 2.57-2.55 (m, 1H), 0.75 (d, J=6.1, 3H). Cis isomer as an offwhite solid (914 mg), ¹H NMR (CDCl₃): 7.42-7.36 (m, 4H), 7.28-7.22 (m,4H), 7.18-7.16 (m, 2H), 4.37 (s, 1H), 4.30-4.27 (m, 1H), 3.46-3.42 (m,1H), 3.26-3.24 (m, 1H), 3.06-3.04 (m, 1H), 0.74 (d, J=6.5 Hz, 3H).

Step C. Preparation of(±)-trans-1-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared according to Example 212 Steps B-C using the trans-isomer fromStep B. MS (ESI): mass calcd. for C₁₇H₁₇BrFNO₂, 365.0; m/z found, 366.1[M+H]⁺. ¹H NMR (MeOD): 7.43-6.95 (m, 7H), 5.12 (s, 2H), 4.68-4.62 (m,1H), 4.32-4.25 (m, 1H), 3.98-3.92 (m, 1H), 3.75-3.68 (m, 1H), 1.44 (d,J=6.7 Hz, 3H).

Example 220cis-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared from cis-(±)-1-benzyl-2-methyl-azetidin-3-ol according toExample 219. MS (ESI): mass calcd. for C₂₄H₂₃BrFNO₂, 455.1; m/z found,456.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-6.94 (m, 11H), 6.78-6.69 (m, 2H),5.08 (s, 2H), 4.78-4.72 (m, 1H), 3.76-3.62 (m, 3H), 3.54-3.48 (m, 1H),3.34-3.26 (m, 1H), 1.20 (d, J=6.4 Hz. 3H).

Example 221trans-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared from trans-(±)-1-benzyl-2-methyl-azetidin-3-ol according toExample 219. MS (ESI): mass calcd. for C₂₄H₂₃BrFNO₂, 455.1; m/z found,456.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.22 (m, 5H), 7.17-7.16 (m, 2H),7.05-6.96 (m, 2H), 6.84 (d, J=2.2 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.07(s, 2H), 4.33 (q, J=6.0 Hz, 1H), 3.82-3.80 (m, 2H), 3.57 (d, J=6.9 Hz,1H), 3.41-3.39 (m, 1H), 2.87 (t, J=7.0 Hz, 1H), 1.21 (d, J=6.2 Hz, 3H).

Example 222 3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine

Step A: Preparation of 1-phenyl-azetidin-3-ol

The mixture of azetidin-3-ol (2 mmol), bromobenzene (2 mmol), Pd(OAc)₂(0.1 mmol), 2-(di-tert-butylphosphino)biphenyl (0.2 mmol) and NaOtBu (3mmol) in toluene (3 mL) was heated at 100° C. for 1 h. The mixture wascooled to rt and purified via PTLC providing the title compound (15 mg).

Step B: Preparation of3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine

The mixture of the title compound of Step A (15 mg),3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (0.2 mmol) and cyanomethylenetri-n-butylphosphorane (0.2 mmol) intoluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. Themixture was cooled to rt and purified via PTLC providing the titlecompound (20 mg). This compound was dissolved in CH₂Cl₂ (5 mL) and TFA(1 mL) was added. The mixture was stirred at rt for 4 h and concentratedto provide the title compound (25 mg). MS (ESI): mass calcd. forC₁₈H₁₉ClN₂O₂, 330.1; m/z found, 331.1 [M+H]⁺. ¹H NMR (MeOD): 7.26-6.58(m, 8H), 5.20-5.05 (m, 2H), 4.55-4.45 (m, 2H), 4.37-4.28 (m, 2H),4.25-4.16 (m, 2H), 3.88-3.85 (m, 2H).

Examples 223-225 were prepared similar to Example 222 using theappropriately substituted hydroxyazetidine.

Example 223(±)-3-[5-Chloro-2-(trans-1-benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from trans-(±)-1-benzyl-2-methyl-azetidin-3-ol. MS (ESI): masscalcd. for C₂₀H₂₃ClN₂O₂, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (MeOD):7.61-7.43 (m, 5H), 7.03-6.87 (m, 3H), 5.23-5.16 (m, 1H), 4.88-4.78 (m,1H), 4.76-4.65 (m, 1H), 4.63-4.45 (m, 5H), 4.29-4.19 (m, 2H), 4.18-4.09(m, 1H), 1.40 (d, J=6.7 Hz, 3H).

Example 224 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from 1-isopropyl-azetidin-3-ol. MS (ESI): mass calcd. forC₁₅H₂₁ClN₂O₂, 296.1; m/z found, 297.0 [M+H]⁺. ¹H NMR (MeOD): 7.70 (dd,J=8.7, 2.5 Hz, 1H), 6.78-6.67 (m, 2H), 5.04-4.97 (m, 1H), 4.76-4.67 (m,1H), 3.98-3.92 (m, 2H), 3.80-3.67 (m, 4H), 3.34-3.26 (m, 2H), 2.53-2.46(m, 1H), 0.98 (d, J=6.3 Hz, 6H).

Example 2253-[5-Chloro-2-(1-benzhydryl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from 1-benzhydryl-azetidin-3-ol. MS (ESI): mass calcd. forC₂₅H₂₅ClN₂O₂, 420.2; m/z found, 421.0 [M+H]⁺. ¹H NMR (MeOD): 7.58-7.39(m, 10H), 7.02-6.81 (m, 3H), 5.81 (s, 1H), 5.19-5.10 (m, 2H), 4.67-4.50(m, 4H), 4.39-4.31 (m, 2H), 4.23-4.16 (m, 2H).

Example 226 3-[5-Chloro-2-(1-azetidin-3-ol)-phenoxy]-azetidine

Prepared according to the procedure of Example 222 Step B using3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): masscalcd. for C₁₂H₁₅ClN₂O₂, 254.1; m/z found, 255.1 [M+H]⁺. ¹H NMR (MeOD):7.00 (dd, J=8.6, 2.4 Hz, 1H). 6.91 (d, J=2.4 Hz, 1H), 6.83 (d, J=8.6 Hz,1H), 5.22-5.11 (m, 2H), 4.62-4.53 (m, 4H), 4.31-4.22 (m, 4H).

Example 2273-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine

To the title compound of Step 226 (100 mg) in CH₂Cl₂ (50 mL) was addedacetone (100 μL) and NaBH₃CN (1 mL, 1M in CH₂Cl₂). The mixture wasstirred at rt for 16 h. Then, NaOH solution (2 mL, 1M in H₂O) was added.After 1 h, the organic layer was separated and concentrated. PTLCprovided the title compound (20 mg). MS (ESI): mass calcd. forC₁₈H₂₇ClN₂O₂, 338.2; m/z found, 339.3 [M+H]⁺. ¹H NMR (CDCl₃): 6.85 (dd,J=8.6, 2.4 Hz, 1H). 6.63 (d, J=2.4 Hz, 1H), 6.58 (d, J=8.6 Hz, 1H),4.83-4.67 (m, 2H), 3.96-3.76 (m, 4H), 3.26-3.05 (m, 4H), 2.47-2.38 (m,2H), 1.00 (d, J=6.1 Hz, 12H).

Example 228 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine

Step A: Preparation of 3-phenyl-cyclobutanol

To the solution of 3-phenyl-cyclobutanone (100 mg) in THF (10 mL) wasadded LiAlH₄ (0.2 mL, 2M in THF). The mixture was stirred at rt for 2 h,then 2M NaOH (1 mL) was added. The organic layer was concentrated andpurified by PTLC providing the title compound (80 mg).

Step B: Preparation of3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine

The mixture of the title compound of Step A (80 mg),3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (200 mg) and cyanomethylenetri-n-butylphosphorane (1.0 mmol) intoluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. Themixture was cooled to rt and purified via PTLC providing3-[5-chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester (120 mg). The ester was re-dissolved into CH₂Cl₂(10 mL), and TFA (2 mL) was added. The mixture was stirred at rt for 4 hthen concentrated to give the title compound (168 mg). MS (ESI): masscalcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.1 [M+H]⁺. ¹H NMR (MeOD):7.26-6.64 (m, 8H), 5.30-5.15 (m, 2H), 4.95-4.83 (m, 2H), 4.60-4.52 (m,1H), 3.78-3.65 (m, 1H), 2.68-2.58 (m, 4H).

Example 2293-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine

Step A: Preparation of 1-tert-butyl-azetidin-3-ol

To a solution of tert-butylamine (10 mmol) in isopropylalcohol (20 mL)was added dropwise epichlorohydrine (10 mmol). The mixture was stirredat 25° C. for 16 h. After concentration, the residue was re-dissolved inacetonitrile (20 mL) and triethylamine (20 mmol) was added. The mixturewas heated at 100° C. for 24 h, cooled to rt and filtered. The filtratewas concentrated providing 1-tert-butyl-azetidin-3-ol (1.1 g). MS (ESI):mass calcd. for C₇H₁₅NO, 129.1; m/z found, 130.1 [M+H]⁺. ¹H NMR (CDCl₃):6.15-5.70 (br s, 1H), 4.84-4.72 (m, 1H), 4.24-4.12 (m, 2H), 4.03-3.87(m, 2H), 1.37 (s, 9H).

Step B: Preparation of3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine

To a solution of the title compound of Step A (3 mmol), andtriethylamine (6 mmol) in CH₂Cl₂ (50 mL), was added MeSO₃Cl (4 mmol).The mixture was stirred at 25° C. for 16 h. After concentration, ⅓ ofthe residue was dissolved in MeCN (20 mL). Next,5-bromo-2-(3-fluoro-benzyloxy)-phenol (0.5 mmol) and K₂CO₃ (2 mmol) wereadded. The mixture was stirred at 100° C. for 16 h, concentrated andpurified via PTLC providing the title compound (189 mg). MS (ESI): masscalcd. for C₂OH₂₃BrFNO₂, 407.1; m/z found, 408.0 [M+H]⁺. ¹H NMR (CDCl₃):7.37-7.28 (m, 1H), 7.19-7.12 (m, 2H), 7.04-6.95 (m, 2H), 6.84-6.63 (m,2H), 5.08 (s, 2H), 4.78-4.48 (m, 1H), 3.68-3.62 (m, 2H), 3.35-3.26 (m,2H), 1.00 (s, 9H).

Example 230-231 was prepared by the procedure of Example 229 using theappropriately substituted phenols.

Example 2301-tert-Butyl-3-[5-chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found, 413.9 [M+H]⁺.¹H NMR (CDCl₃): 7.75-7.46 (m, 4H), 6.90-6.65 (m, 3H), 5.12 (s, 2H),4.80-4.71 (m, 1H), 3.71-3.62 (m, 2H), 3.35-3.26 (m, 2H), 0.99 (s, 9H).

Example 2311-tert-Butyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₂H₂₅ClF₃NO₂, 427.2; m/z found, 428.3 [M+H]⁺.¹H NMR (CDCl₃): 7.68-7.42 (m, 4H), 6.78-6.62 (m, 3H), 5.32-5.23 (m, 1H),4.78-4.68 (m, 1H), 3.70-3.62 (m, 2H), 3.33-3.25 (m, 2H), 1.65 (d, J=6.4Hz, 3H), 0.99 (s, 9H).

Example 2323-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine

Step A: Preparation of3-(Methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butylester

To a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester(3.5 g, 17 mmol) in DMF (50 mL) was added O,N-dimethyl-hydroxylaminehydrochloride (3.4 g, 34 mmol), triethylamine (9.6 mL, 69 mmol), HATU(13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturatedNaHCO₃ solution and ethyl acetate were added. The aqueous portion wasextracted three times with ethyl acetate. The combined organic fractionswere dried (Na₂SO₄) and concentrated and the crude product was purifiedusing RP HPLC (basic conditions) to provide the title compound (3.5 g,83%) MS (ESI): mass calcd. for C₁₁H₂₀N₂O₄, 244.1; m/z found, 189.1[M-t-Bu]⁺. ¹H NMR (CDCl₃): 4.14-4.03 (m, 2H), 4.05 (t, J=8.7 Hz, 2H),3.66 (s, 3H), 3.63-3.59 (m, 1H), 3.21 (s, 1H), 1.43 (s, 9H).

Step B: Preparation of 3-(2-Methoxy-benzoyl)-azetidine-1-carboxylic acidtert-butyl ester

To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylicacid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0° C.was added 2-methoxylphenylmagnesium bromide (1.0 M in THF, 17 mL, 17mmol). The reaction was allowed to slowly warm to rt and stirred for 36h. Then a solution of 1M KHSO₄ and EtOAc were added and the aqueousportion was extracted once with EtOAc. The combined organic fractionswere dried (Na₂SO₄) and concentrated to provide the title compound. Thismaterial was used in subsequent reactions without additionalpurifications. MS (ESI): mass calcd. for C₁₆H₂₁NO₄, 291.1; m/z found,236.1 [M-t-Bu]⁺. ¹H NMR (CDCl₃): 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.51(ddd, J=8.5, 7.3, 1.8 Hz, 1H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H),3.90 (s, 3H), 1.44 (s, 9H).

Step C: Preparation of 3-(2-Methoxy-benzyl)-azetidine-1-carboxylic acidtert-butyl ester

To a solution of 3-(2-methoxy-benzoyl)-azetidine-1-carboxylic acidtert-butyl ester (2.1 g, 7.2 mmol) in methanol (50 mL) was added sodiumborohydride (1.08 g, 28.8 mmol). After stirring for 36 h, saturatedsodium bicarbonate solution and EtOAc were added. The aqueous portionwas extracted three times with EtOAc and the combined organic were dried(Na₂SO₄) and concentrated. To a solution of this material in ethanol (50mL) was added 10% Pd/C. This reaction was then placed on a Parrhydrogenation apparatus with 60 psi of hydrogen gas. After 72 h, thereaction mixture was filtered through a pad of Celite and the filtrateconcentrated. The crude product was purified by RP HPLC (basicconditions) to provide the title compound (370 mg, 19%). MS (ESI): masscalcd. for C₁₆H₂₃NO₃, 277.2; m/z found, 222.2 [M-t-Bu]⁺. ¹H NMR (CDCl₃):7.23-7.10 (m, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.92-6.77 (m, 2H), 3.96 (t,J=8.0 Hz, 2H), 3.81 (s, 3H), 3.65-3.63 (m, 2H), 2.94-2.78 (m, 5H), 1.44(s, 9H).

Step D: Preparation of2,2,2-Trifluoro-1-[3-(2-methoxy-benzyl)-azetidin-1-yl]-ethanone

To a solution of 3-(2-methoxy-benzyl)-azetidine-1-carboxylic acidtert-butyl ester (370 mg, 1.3 mmol) in DCM (10 mL) was added TFA (3 mL).After stirring for 16 h, TLC analysis indicated complete consumption ofthe starting material. To quench the reaction, saturated NaHCO₃ solutionand EtOAc were added. The aqueous portion was extracted twice with EtOAcand the combined organic extracts were dried (Na₂SO₄) and concentrated.To a solution of this material in DCM (20 mL) was added triethylamine(370 μL, 2.60 mmol) followed by trifluoroacetic anhydride (204 μL, 1.50mmol). After 1 h, saturated NaHCO₃ solution and EtOAc were added. Theaqueous portion was extracted twice with EtOAc and the combined organicextracts were dried (Na₂SO₄) and concentrated to provide the titlecompound (274 mg, 75%). MS (ESI): mass calcd. for C₁₃H₁₄F₃NO₂, 273.1;m/z found, 274.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.26-7.20 (m, 1H), 7.07 (dd,J=7.4, 1.6 Hz, 1H), 6.94-6.82 (m, 2H), 4.41 (dd, J=9.6, 8.4 Hz, 1H),4.23-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.93-3.84 (m, 1H), 3.82 (s, 3H),3.18-3.00 (m, 1H), 2.95-2.91 (m, 2H).

Step E: Preparation of1-[3-(5-Bromo-2-methoxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To a solution of2,2,2-trifluoro-1-[3-(2-methoxy-benzyl)-azetidin-1-yl]-ethanone (95 mg,0.35 mmol) in acetone (2 mL) and water (2 mL) was added NaBr (143 mg,1.40 mmol) followed by Oxone (210 mg, 0.35 mmol). After 5 h, 10% sodiummetabisulfite solution was added. After 1 h, EtOAc was added and theaqueous portion extracted twice with EtOAc. The combined organics weredried (Na₂SO₄) and concentrated. The crude product was purified by RPHPLC (basic conditions) to provide the title compound (66 mg, 53%). MS(ESI): mass calcd. for C₁₃H₁₃BrF₃NO₂, 352.1; m/z found, 354.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.75(t, J=10.2 Hz, 1H), 4.43 (dd, J=9.6, 8.4 Hz, 1H), 4.26-4.14 (m, 1H),4.09 (dd, J=9.6, 5.7 Hz, 1H), 3.89 (dd, J=10.7, 5.7 Hz, 1H), 3.81 (s,3H), 3.14-2.96 (m, 1H), 2.90 (d, J=7.8 Hz, 2H).

Step F: Preparation of1-[3-(5-Bromo-2-hydroxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To a solution of1-[3-(5-bromo-2-methoxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone(66 mg, 0.19 mmol) in dry DCM (10 mL) at 0° C. was added BBr₃ (1.0 M inDCM, 370 mL, 0.37 mmol). After warming to rt overnight, saturated NaHCO₃solution and EtOAc were added. The aqueous portion was extracted twicewith EtOAc and the combined organic extracts were dried (Na₂SO₄) andconcentrated to provide the title compound (59 mg, 92%). MS (ESI): masscalcd. for C₁₂H₁₁BrF₃NO₂, 337.0; m/z found, 338.0 [M+H]⁺. ¹H NMR(CDCl₃): 7.23-7.10 (m, 2H), 6.70 (t, J=8.7 Hz, 1H), 4.53-4.40 (m, 1H),4.27-4.11 (m, 2H), 3.97 (dd, J=10.7, 6.0 Hz, 1H), 3.17-3.01 (m, 1H),3.01-2.78 (m, 2H).

Step G: Preparation of1-{3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1-yl}-2,2,2-trifluoro-ethanone

To a solution of1-[3-(5-bromo-2-hydroxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone(59 mg, 0.17 mmol) in DMF (10 mL) was added KI (40 mg, 0.24 mmol),Cs₂CO₃ (170 mg, 0.51 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (56mg, 0.24 mmol). After 16 h, saturated sodium bicarbonate solution andEtOAc were added. The aqueous portion was extracted three times withEtOAc and the combined organic were dried (Na₂SO₄) and concentrated. Thecrude product was purified by RP HPLC (basic conditions) to provide thetitle compound (76 mg, 91%). MS (ESI): mass calcd. for C₁₈H₁₄BrF₆NO₃,486.2; m/z found, 488.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34 (dd, J=8.7, 2.5 Hz,1H), 7.21 (d, J=2.5 Hz, 1H), 6.89-6.76 (m, 2H), 6.48 (d, J=3.4 Hz, 1H),5.02 (s, 2H), 4.40 (dd, J=9.6, 8.4 Hz, 1H), 4.22-4.11 (m, 1H), 4.08-4.02(m, 1H), 3.84 (dd, J=10.7, 5.7 Hz, 1H), 3.11-2.97 (m, 1H), 2.97-2.82 (m,2H).

Step H: Preparation of3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine

To a solution of1-{3-[5-bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1-yl}-2,2,2-trifluoro-ethanone(76 mg, 0.16 mmol) in methanol (10 mL) was added K₂CO₃ (94 mg, 0.70mmol). After 1 h, TLC analysis indicated complete consumption of thestarting material. Brine and EtOAc were added to the reaction mixtureand the aqueous portion was extracted with EtOAc (3×). The combinedorganic layers were dried. The crude product was purified by RP HPLC(basic conditions) to provide the title compound (50 mg, 76%). MS (ESI):mass calcd. for C₁₆H₁₅BrF₃NO₂, 390.2; m/z found, 393.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.50-7.41 (m, 1H), 7.35-7.26 (m, 1H), 6.89-6.79 (m, 2H), 6.53(s, 1H), 5.05 (s, 2H), 4.43-4.20 (m, 1H), 3.63 (t, J=8.2 Hz, 2H), 3.44(t, J=7.7 Hz, 2H), 2.85 (d, J=7.6 Hz, 2H).

Example 233 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidine

Prepared similar to Example 1 using3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI):mass calcd. for C₁₇H₁₇BrClNO₂, 381.0: m/z found, 382.1 [M+H]⁺. ¹H NMR(CDCl₃): 7.45 (s, 1H), 7.35-7.21 (m, 3H), 7.15-6.96 (m, 2H), 6.77 (d,J=8.5, 1H), 5.04 (s, 2H), 4.16 (d, J=6.4, 2H), 3.81 (m, 2H), 3.63 (m,1H), 3.62-3.52 (m, 1H), 3.21 (m, 1H), 2.17 (m, 1H).

Example 2343-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxvmethyl]-1-methyl-azetidine

Prepared from Example 233 using general procedure 5. MS (ESI): masscalcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1 [M+H]⁺. ¹H NMR(CDCl₃): 7.52 (d, J=2.5, 1 H), 7.40 (s, 1H), 7.36-7.22 (m, 4H), 6.74 (d,J=8.7, 1H), 5.04 (s, 2H), 4.45 (s, 2H), 4.23-4.15 (m, 1H), 3.64 (s, 2H),2.93 (s, 2H), 2.35 (s, 3H).

Example 2353-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

Step A: Preparation of1-Boc-3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

The mixture of the title compound of Example 215 Step B (2.3 mmol),5-bromo-2-(3-chloro-benzyloxy)-phenol (1.3 mmol), andcyanomethylenetri-n-butylphosphorane (2 mmol) in toluene (5 mL) washeated at 150° C. in a microwave reactor for 1 h. The mixture was cooledto rt and purified by PTLC providing the title compound (580 mg). MS(ESI): mass calcd. for C₂₂H₂₅BrClNO₅, 497.1; m/z found, 504.2[M-OH+Na]⁺. ¹H NMR (CDCl₃): 7.52-7.23 (m, 4H), 6.99-6.68 (m, 3H),5.70-5.10 (br S, 1H), 5.04 (s, 2H), 4.99-4.97 (m, 2H), 4.50-4.46 (m,4H), 1.45 (s, 9H)

Step B: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

The the title compound of Step A (160 mg) was dissolved in CH₂12 (20mL), and TFA (3 mL) was added. The mixture was stirred at rt for 4 h andconcentrated. The resulting residue was dissolved into MeOH (20 mL), andDowex 66 ion-exchange resin (Dowex hydroxide, weakly basic anion,Macroporous) was added to adjust the pH to 7. The resin was filtered andthe filtrate concentrated providing the title compound (120 mg). MS(ESI): mass calcd. for C₁₇H₁₇BrClNO₃, 397.0; m/z found, 382.2 [M-OH+H]+.¹H NMR (MeOD): 7.52-7.28 (m, 4H), 6.97-6.81 (m, 3H), 5.18-5.15 (m, 2H),5.12 (s, 2H), 4.73-4.68 (m, 4H).

Example 2363-[1-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol

Prepared according to Example 235 using3-ethyl-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester. MS(ESI): mass calcd. for C₁₈H₁₉BrClNO₃, 411.0; m/z found, 396.0 [M-OH+H]⁺.¹H NMR (MeOD): 7.52-7.27 (m, 4H), 6.98-6.80 (m, 3H), 5.57-5.48 (m, 1H),5.12 (s, 2H), 4.73-4.61 (br s, 4H), 1.63-1.57 (m, 3H).

Example 237 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

Step A: Preparation of [5-Bromo-2-(3-chloro-benzyloxy)-phenyl]-methanol

To a solution of 5-bromo-2-(3-chloro-benzyloxy)-benzaldehyde (6.0 g,18.4 mmol) in MeOH (90 mL) at rt was added NaBH₄ (1.07 g, 27.7 mmol)over 1 h. After 18 h at rt, H₂O was added (5 mL) and the reactionconcentrated to a residual mass, which was dissolved into EtOAc (150mL). This EtOAc solution was washed with H₂O (2×100 mL) and dried toyield the title compound as a light yellow (6.0 g, 100%). MS (ESI): masscalcd. for C₁₄H₁₂BrClO, 327.6; m/z found, 328.3 [M+H]⁺. ¹H NMR (CDCl₃)7.48 (d, J=2.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.76 (d, J=8.7 Hz, 1H), 5.07(d, J=19.2 Hz, 2H), 4.69 (d, J=17.5 Hz, 2H), 2.15 (t, J=10.0 Hz, 1H).

Step B. 5-Bromo-2-(3-chloro-benzyloxy)-benzyl chloride

The title compound of Step A was dissolved into CH₂Cl₂ (8 mL) andthionyl chloride (114 mg, 0.95 mmol) was added at rt. The reactionmixture was stirred for 2 h and concentrated to yield the title compound(300 mg). ¹H NMR (CDCl₃): 7.51 (d, J=2.5 Hz, 1H), 7.48-7.22 (m, 6H),6.76 (t, J=11.1 Hz, 1H), 5.14-4.99 (m, 2H), 4.65 (d, J=14.7 Hz, 2H).

Step C. 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

To a DMF (5 mL) solution of 3-hydroxy-azetidine-1-carboxylic acidtert-butyl ester (150 mg, 0.87 mmol) at rt was added 60% NaH (36 mg,0.91 mmol). The reaction mixture was stirred at rt for 0.5 h. Then a DMFsolution of the title compound of Step B (300 mg, 0.87 mmol) was added.After 18 h, the reaction mixture was partitioned between EtOAc and H₂O.The organic phase was dried and concentrated to yield the title compound(380 mg). This material was purified by chromatography (SiO₂) using0-25% EtOAc in hexanes to give3-[5-bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine-1-carboxylic acidtert-butyl ester (70 mg, 37%). This compound was treated with 4M HCl indioxane and stirred 6 h at rt and concentrated. Purification by RP HPLC(basic system) gave the title compound (26 mg, 7%) MS (ESI): mass calcd.for C₁₇H₁₇BrClNO₂, 381.7; m/z found, 383.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.52(d, J=2.5 Hz, 1H), 7.41 (s, 1H), 7.36-7.21 (m, 4H), 6.74 (d, J=8.7 Hz,1H), 5.03 (s, 2H), 4.49-4.39 (m, 3H), 3.68 (m, 4H), 1.75 (s, 1H).

Example 238 3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

Prepared according to Example 237 using5-chloro-2-(3-chloro-benzyloxy)-benzaldehyde. MS (ESI): mass calcd. forC₁₇H₁₇Cl₂NO₂, 337.06; m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.15(m, 6H), 6.79 (d, J=8.7 Hz, 1H), 5.04 (s, 2H), 4.49-4.39 (m, 3H),3.71-3.67 (m, 3H), 1.92 (m, 1H), 1.90-1.83 (m, 1H).

Example 2395-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazole

Step A: Preparation of3-(5-Chloro-2-ethoxycarbonylmethoxy-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butylester (1.5 g, 5.0 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.1 g, 6.4mmol), KI (0.84 g, 5.0 mmol) and bromoethyl acetate (0.84 g, 0.55 mL,5.0 mmol). After 18 h, H₂O was added and the mixture extracted withEtOAc (2×). The combined organics were washed with brine and dried.Silica gel chromatography (5-30% EtOAc in hexanes) gave 1.95 g (99%) ofthe title compound as a clear oil. ¹H NMR (CDCl₃): 6.91 (dd, J=8.7, 2.4Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.91-4.87 (m,1H), 4.65 (s, 2H), 4.32-4.25 (m, 4H), 4.01 (dd, J=10.5, 4.2 Hz, 2H),1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).

Step B: Preparation of3-(2-Carboxymethoxy-5-chloro-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester

To the title compound from Step A (1.70 g, 4.40 mmol) in MeOH (10 mL)was added 4N NaOH (10 mL). After 2 h, CH₂Cl₂ was added and the mixtureacidified with 1 N KHSO₄ (50 mL) then extracted with CH₂Cl₂ (2×). Thecombined organics were dried to give a 0.90 g (57%) of the titlecompound as a white solid that was used without further purification. MS(ESI): mass calcd. for C₁₆H₂₀ClNO₆, 357.1; m/z found, 380.1 [M+Na]⁺. ¹HNMR (400 MHz): 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H),6.59 (d, J=2.3 Hz, 1H), 4.92-4.86 (m, 1H), 4.67 (s, 2H), 4.31 (dd,J=9.9, 6.5 Hz, 2H), 4.07 (dd, J=10.0, 4.1 Hz, 2H), 1.45 (s, 9H).

Step C: Preparation of3-[5-Chloro-2-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To the title compound of Step B (0.15 g, 0.42 mmol) in CH₂Cl₂ (4 mL) wasadded DMF (catalytic) and 2M COCl₂ in CH₂Cl₂ (0.3 mL, 0.6 mmol). After 2h, the reaction was concentrated and THF (2 mL) was added. This solutionwas added to N-hydroxy-acetamidine (0.035 g, 0.46 mmol) andN,N-diisopropylethylamine (0.065 g, 0.088 mL, 0.50 mmol) in THF (2 mL).The mixture was then heated for 20 min at 155° C. in a microwavereactor, cooled to rt and concentrated. Silica gel chromatography (5-30%EtOAc in hexanes) gave 0.155 g (93%) of the title compound as a clearoil. MS (ESI): mass calcd. for C₁₈H₂₂ClN₃O₅, 395.1; m/z found, 295.3[M−100]⁺. ¹H NMR (400 MHz): 6.94 (d, J=8.6 Hz, 1H), 6.91 (dd, J=8.6, 2.2Hz, 1H), 6.57 (d, J=2.1 Hz, 1H), 5.27 (s, 2H), 4.89-4.85 (m, 1H),4.32-4.29 (m, 2H), 4.04 (dd, J=10.4, 4.2 Hz, 2H), 2.43 (s, 3H), 1.45 (s,9H).

Step D: Preparation of5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazolehydrochloride

Prepared from the title compound of Step B using general procedure 1. MS(ESI): mass calcd. for C₁₃H₁₄ClN₃O₃, 295.1; m/z found, 296.2 [M+H]⁺. ¹HNMR (DMSO-D₆): 9.30 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.05 (dd, J=8.7,2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.52 (s, 2H), 5.10-5.05 (m, 1H),4.42 (dd, J=12.5, 6.7 Hz, 2H), 4.01 (dd, J=12.5, 4.8 Hz, 2H) 2.36 (s,3H).

The compounds in Examples 240-243 were synthesized according to Example239 using the appropriately substituted N-hydroxyamidine.

Example 2405-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl-[1,2,4]oxadiazole

MS (ESI): mass calcd. for C₁₆H₁₈ClN₃O₃, 335.1; m/z found, 336.2 [M+H]⁺.¹H NMR (CDCl₃): 6.95 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.6, 2.3 Hz, 1H),6.62 (s, 1H), 5.28 (s, 2H), 4.99-4.89 (m, 1H), 3.98-3.66 (m, 5H),2.41-2.36 (m, 4H), 2.17-1.98 (m, 2H).

Example 2415-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl-[1,2,4]oxadiazolehydrochloride

MS (ESI): mass calcd. for C₁₅H₁₆ClN₃O₃, 321.1; m/z found, 322.2 [M+H]⁺.¹H NMR (DMSO-D₆): 9.31 (s, 2H), 7.12 (d, J=8.8 Hz, 1H), 7.05 (dd, J=8.7,2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.49 (s, 2H), 5.09-5.04 (m, 1H),4.42 (dd, J=12.2, 6.6 Hz, 2H), 4.03-3.99 (m, 2H), 2.17-2.13 (m, 1H),1.11-1.07 (m, 2H), 0.90-0.87 (m, 2H).

Example 2425-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl-[1,2,4]oxadiazolehydrochloride

MS (ESI): mass calcd. for C₁₅H₁₈ClN₃O₃, 323.1; m/z found, 324.2 [M+H]⁺.¹H NMR (DMSO-D₆): 9.28 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7,2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.51 (s, 2H), 5.10-5.05 (m, 1H),4.43 (dd, J=12.3, 6.6 Hz, 2H), 4.02 (dd, J=12.3, 4.7 Hz, 2H), 3.12-3.07(m, 1H), 1.28 (d, J=6.9 Hz, 6H).

Example 2435-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1,2,4]oxadiazolehydrochloride

MS (ESI): mass calcd. for C₁₄H₁₆ClN₃O₃, 309.1; m/z found, 310.2 [M+H]⁺.¹H NMR (DMSO-D₆): 9.34 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7,2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.51 (s, 2H), 5.10-5.05 (m, 1H),4.42 (dd, J=12.6, 6.7 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 2H), 2.75 (q,J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 2H).

Compounds in Examples 244-278 were synthesized according to generalprocedure 6.

Example 244 3-(5-Bromo-2-phenoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₅H₁₄BrNO₂, 320.2; m/z found, 322.1 [M+H]⁺.¹H NMR (CDCl₃): 7.32-7.28 (m, 2H), 7.07-7.05 (m, 2H), 6.94-6.92 (m, 2H),6.88-6.84 (m, 2H), 4.97-4.91 (m, 1H), 3.85-3.81 (m, 2H), 3.71-3.67 (m,2H).

Example 245 3-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃Br₂NO₂, 399.1; m/z found, 401.0 [M+H]⁺.¹H NMR (CDCl₃): 7.21-7.12 (m, 2H), 7.09 (dd, J=8.5, 2.2 Hz, 1H),7.04-6.98 (m, 1H), 6.91 (d, J=8.5, 1H), 6.88-6.77 (m, 2H), 4.96-4.92 (m,1H), 3.90-3.78 (m, 2H), 3.72-3.60 (m, 2H).

Example 246 3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine

MS (ESI) mass calcd. for C₁₅H₁₃BrFNO₂, 337.01; m/z found, 338.3 [M+H]⁺.¹H NMR (CD₃OD) 7.37-7.21 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.03 (d, J=8.6Hz, 1H), 6.83 (t, J=8.4, 2.4 Hz, 1H), 6.75-6.63 (m, 2H), 5.15 (m, 1H),4.47 (dd, J=12.4, 6.6 Hz, 2H), 4.05 (dd, J=12.4, 4.7 Hz, 2H).

Example 247 3-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine

MS (ESI) mass calcd. for C₁₆H₁₆BrFNO₂, 333.04; m/z found, 334.1 [M+H]⁺.¹H NMR (CD₃OD) 7.25-7.10 (m, 3H), 6.92 (dd, J=12.9, 8.1 Hz, 2H),6.80-6.64 (m, 2H), 5.19-5.03 (m, 1H), 4.45 (dd, J=12.7, 6.7 Hz, 2H),4.09 (dd, J=12.6, 4.9 Hz, 2H).

Example 248 3-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy]-azetidine

MS (ESI):mass calcd. for C₁₆H₁₆BrNO₃, 350.2; m/z found, 351.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.18 (t, J=8.1 Hz, 1H), 7.06 (dd, J=8.5, 2.2 Hz, 1H), 6.88(d, J=8.5 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.62 (dd, J=8.2, 1.7 Hz, 1H),6.53-6.45 (m, 2H), 5.00-4.90 (m, 1H), 3.95-3.62 (m, 7H).

Example 249 3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrFNO₂, 338.2; m/z found, 339.1 [M+H]⁺.¹H NMR (CDCl₃): 7.05 (dd, J=8.5, 2.2 Hz, 1H), 7.01-6.97 (m, 2H),6.90-6.88 (m, 2H), 6.82 (dd, J=5.4, 3.1 Hz, 2H), 4.99-4.90 (m, 1H),3.92-3.64 (m, 4H).

Example 250 3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃Br₂NO₂, 399.1; m/z found, 401.0 [M+H]⁺.¹H NMR (CDCl₃): 7.43-7.33 (m, 2H), 7.08 (dd, J=8.5, 2.3 Hz, 1H), 6.88(d, J=8.5 Hz, 1H), 6.83-6.78 (m, 3H), 4.99-4.90 (m, 1H), 3.95-3.55 (m,4H).

Example 251 3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrClNO₂, 354.6; m/z found, 355.0 [M+H]⁺.¹H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.10 (dd,J=8.0, 1.9 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.2 Hz, 1H), 6.85(dd, J=8.3, 2.4 Hz, 1H), 5.18-5.10 (m, 1H), 4.50-4.41 (m, 2H), 4.07-4.04(m, 2H).

Example 252 3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrClNO₂, 354.6; m/z found, 355.0 [M+H]⁺.¹H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.10 (dd,J=8.0, 1.9 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.2 Hz, 1H), 6.85(dd, J=8.3, 2.4 Hz, 1H), 5.18-5.10 (m, 1H), 4.50-4.41 (m, 2H), 4.07-4.04(m, 2H).

Example 253 3-[5-Bromo-2-(3-trifluoromethoxy-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₃BrF₃NO₃, 403.0; m/z found, [M+H]⁺. ¹HNMR (MeOD): 7.41 (t, J=8.3 Hz, 1H), 7.31-7.13 (m, 2H), 7.06-7.02 (m,1H), 7.02-6.97 (m, 1H), 6.93-6.78 (m, 2H), 5.21-5.09 (m, 1H), 4.50-4.47(m, 2H), 4.06-4.03 (m, 2H), 3.34-3.24 (m, 1H).

Example 254 3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆BrNO₂, 369.0; m/z found, 370.1 [M+H]⁺.¹H NMR (MeOD): 7.92-7.77 (m, 2H), 7.70 (d, J=8.1 Hz, 1H), 7.49-6.97 (m,7H), 5.20-5.12 (m, 1H), 4.44 (dd, J=12.5, 6.6 Hz, 2H), 4.05 (dd, J=12.5,5.0 Hz, 2H).

Example 255 3-[5-Bromo-2-(naphthalen-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆BrNO₂, 369.0; m/z found, 370.1 [M+H]⁺.¹H NMR (MeOD): 8.25-8.16 (m, 1H), 7.95-7.85 (m, 1H), 7.65-7.16 (m, 6H),6.95-6.72 (m, 2H), 5.21-5.12 (m, 1H), 4.42 (m, 2H), 4.05 (dd, J=12.5,5.0 Hz, 2H).

Example 256 3-(5-Chloro-2-phenoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₅H₁₄ClNO₂, 275.1; m/z found, 276.1 [M+H]⁺.¹H NMR (CDCl₃): 7.33-7.26 (m, 2H), 7.11-6.99 (m, 1H), 6.99-6.84 (m, 4H),6.70 (d, J=1.3 Hz, 1H), 4.97-4.91 (m, 1H), 3.88-3.79 (m, 2H), 3.75-3.64(m, 2H).

Example 257 3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine maleate

MS (ESI): mass calcd. for C₁₅H₁₃Cl₂NO₂, 309.0; m/z found, 310.1 [M+H]⁺.¹H NMR (CDCl₃): 7.22 (t, J=8.2 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.01(dd, J=8.6 Hz, 2.3 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.89 (t, J=2.1 Hz,1H), 6.80 (dt, J=5.2, 2.5 Hz, 2H), 6.29 (s, 2H), 5.18-5.08 (m, 1H), 4.44(d, J=6.7 Hz, 2H), 4.21 (s, 2H).

Example 258 3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidinetrifluoroacetate

MS (ESI): mass calcd. for C₁₅H₁₃Cl₂NO₂, 309.0; m/z found, 310.8 [M+H]⁺.¹H NMR (CDCl₃): 7.31-7.27 (m, 2H), 7.02 (dd, J=8.7, 2.4 Hz, 1H), 6.91(d, J=8.6 Hz, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J=2.3 Hz, 1H), 5.11-5.06(m, 1H), 4.34 (dd, J=11.8, 6.8 Hz, 2H), 4.14 (dd, J=11.7, 5.5 Hz, 2H).

Example 259 3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₆ClNO₂, 289.1; m/z found, 290.2 [M+H]⁺.¹H NMR (CDCl₃): 7.25 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.0 Hz, 1H), 7.07 (t,J=7.4 Hz, 1H), 6.95 (dd, J=8.7, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H),6.75 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 5.10 (s, 1H), 4.34 (s,2H), 4.19 (s, 2H), 2.24 (s, 3H).

Example 260 3-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆ClNO₂, 325.1; m/z found, 326.2 [M+H]⁺.¹H NMR (MeOD): 7.90-7.79 (m, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.48-7.03 (m,7H), 5.20-5.12 (m, 1H), 4.44 (dd, J=12.6, 6.6 Hz, 2H), 4.05 (dd, J=12.6,5.0 Hz, 2H).

Example 261 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole

A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acidtert-butyl ester (0.5 mmol), 2-chloro-benzothiazole (0.5 mmol), andK₂CO₃ (1 mmol) in CH₃CN (3 mL) was heated at 120-150° C. via Microwavefor 1 h. The mixture was cooled down and separated through PTLCproviding3-[2-(benzothiazol-2-yloxy)-5-chloro-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester (180 mg). The ester was re-dissolved into CH₂Cl₂(20 mL), and CF₃COOH (3 mL) was added. The mixture was stirred at 25° C.for 4 h. After concentration, the title compound was obtained (192 mg).MS (ESI): mass calcd. for C₁₆H₁₃ClN₂O₂S, 332.0; m/z found, 333.1 [M+H]⁺.¹H NMR (MeOD): 7.23-7.07 (m, 4H), 6.92-6.81 (m, 3H), 5.14-5.08 (m, 1H),4.51 (dd, J=12.5, 6.6 Hz, 2H), 4.23 (dd, J=12.5, 5.0 Hz, 2H).

Example 262 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole

MS (ESI): mass calcd. for C₁₆H₁₃ClN₂O₃, 316.1; m/z found, 317.1 [M+H]⁺.¹H NMR (MeOD): 7.83-7.78 (m, 1H), 7.67-7.62 (m, 1H), 7.46-7.41 (m, 2H),7.26-7.21 (m, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H),5.26-5.21 (m, 1H), 4.50 (dd, J=12.7, 6.6 Hz, 2H), 4.07 (dd, J=12.7, 4.8Hz, 2H).

Example 263 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1,8]naphthyridine

MS (ESI): mass calcd. for C₁₇H₁₄ClN₃O₂, 327.1; m/z found, 328.1 [M+H]⁺.¹H NMR (MeOD): 9.06-9.04 (m, 1H), 8.97 (d, J=4.7 Hz, 1H), 8.74 (d, J=8.9Hz, 1H), 7.92 (dd, J=8.1, 5.4 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.25 (d,J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H),5.27-5.18 (m, 1H), 4.46 (dd, J=12.7, 6.6 Hz, 2H), 3.97 (dd, J=12.7, 4.8Hz, 2H).

Example 264 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline

MS (ESI): mass calcd. for C₁₈H₁₅ClN₂O₂, 327.1; m/z found, 328.1 [M+H]⁺.¹H NMR (CDCl₃): 8.75 (s, 1H), 8.12-8.06 (m, 1H), 7.65-7.58 (m, 3H), 7.20(d, J=8.6 Hz, 1H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H),4.99-4.88 (m, 1H), 3.86-3.72 (m, 2H), 3.61-3.47 (m, 2H).

Example 265 4-(5-Chloro-2-phenoxy-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.8; m/z found, 304.2 [M+H]⁺.¹H NMR (CDCl₃): 7.29-7.26 (m, 2H), 7.04-7.01 (m, 1H), 6.99-6.97 (m, 2H),6.93-6.89 (m, 3H), 4.35-4.30 (m, 2H), 2.95-2.91 (m, 2H), 2.62 (ddd,J=12.3, 8.6, 3.3 Hz, 2H), 1.88-1.82 (m, 2H), 1.57-1.45 (m, 2H).

Example 266 (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺.¹H NMR (CDCl₃): 7.09 (t, J=7.7 Hz, 2H), 7.04 (dd, J=8.7, 2.5 Hz, 1H),6.99 (d, J=2.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.84-6.78 (m, 2H), 4.79(dd, J=5.7, 4.4 Hz, 1H), 3.06 (d, J=12.8 Hz, 1H), 2.98-2.89 (m, 1H),2.82-2.71 (m, 2H), 2.32 (s, 3H), 1.99-1.89 (m, 1H), 1.87-1.78 (m, 1H).

Example 267 (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺.¹H NMR (CDCl₃): 7.09 (d, J=8.3 Hz, 2H), 7.04 (dd, J=8.7, 2.5 Hz, 1H),6.98 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.83-6.79 (m, 2H), 4.79(t, J=4.8 Hz, 1H), 3.05 (d, J=12.8 Hz, 1H), 2.97-2.89 (m, 1H), 2.78 (d,J=9.3 Hz, 2H), 2.31 (s, 3H), 1.99-1.89 (m, 1H), 1.86-1.77 (m, 1H).

Example 268 (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine

Prepared from Example 261 using general procedure 5. MS (ESI): masscalcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.2 [M+H]⁺. ¹H NMR (CDCl₃):7.10 (d, J=8.4 Hz, 2H), 7.00 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (d, J=2.5 Hz,1H), 6.87-6.79 (m, 3H), 4.84-4.74 (m, 1H), 2.91 (dd, J=10.6, 6.1 Hz,1H), 2.58 (dd, J=6.9, 6.3 Hz, 2H), 2.54-2.48 (m, 1H), 2.32 (d, J=4.5 Hz,6H), 2.23-2.16 (m, 1H), 1.98-1.86 (m, 1H).

Example 269 (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺.¹H NMR (CDCl₃): 7.07 (dd, J=8.7, 2.5 Hz, 1H), 7.03-6.96 (m, 3H),6.92-6.84 (m, 3H), 4.78 (dd, J=5.9, 4.5 Hz, 1H), 3.04 (d, J=12.8 Hz,1H), 2.95 (dt, J=11.3, 7.4 Hz, 1H), 2.89-2.75 (m, 2H), 2.02-1.92 (m,1H), 1.85-1.77 (m, 1H).

Example 270 (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺.¹H NMR (CDCl₃): 7.06 (dd, J=8.7, 2.5 Hz, 1H), 7.02-6.96 (m, 3H),6.91-6.84 (m, 3H), 4.78 (dd, J=5.8, 4.5 Hz, 1H), 3.05 (d, J=12.8 Hz,1H), 2.96 (dt, J=11.3, 7.4 Hz, 1H), 2.90-2.74 (m, 2H), 2.03-1.92 (m,1H), 1.85-1.77 (m, 1H).

Example 271(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine

Prepared from Example 264 using general procedure 5. MS (ESI): masscalcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.2 [M+H]⁺. ¹H NMR (CDCl₃):7.05-6.96 (m, 3H), 6.94-6.86 (m, 3H), 6.81 (d, J=8.7 Hz, 1H), 4.93-4.53(m, 1H), 2.91 (dd, J=10.6, 6.1 Hz, 1H), 2.63-2.41 (m, 3H), 2.32 (s, 3H),2.23-2.16 (m, 1H), 1.90-1.81 (m, 1H).

Example 272 (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺.¹H NMR (CDCl₃): 7.23 (d, J=6.8 Hz, 1H), 7.11-7.06 (m, 1H), 7.04-6.98 (m,2H), 6.91 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.0 Hz,1H), 4.79 (dd, J=5.6, 4.4 Hz, 1H), 3.04 (d, J=12.9 Hz, 1H), 2.89 (dt,J=11.4, 7.4 Hz, 1H), 2.81-2.71 (m, 2H), 2.29 (s, 3H), 1.98-1.89 (m, 1H),1.85-1.75 (m, 1H).

Example 273 (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺.¹H NMR (CDCl₃): 7.17 (t, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H), 7.04-7.00 (m,1H), 6.91-6.85 (m, 2H), 6.76-6.66 (m, 2H), 4.81-4.75 (m, 1H), 3.03 (d,J=12.8 Hz, 1H), 2.89 (dt, J=11.3, 7.5 Hz, 1H), 2.80-2.70 (m, 2H), 2.31(s, 3H), 1.96-1.88 (m, 1H), 1.85-1.74 (m, 1H).

Example 274(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.2 [M+H]⁺.¹H NMR (CDCl₃): 7.05 (dd, J=8.7, 2.5 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H),6.92 (d, J=8.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.75 (dd, J=6.2, 3.0 Hz,1H), 6.72-6.65 (m, 1H), 4.79 (dd, J=5.8, 4.5 Hz, 1H), 3.07 (d, J=12.8Hz, 1H), 2.98 (dt, J=11.4, 7.4 Hz, 1H), 2.88-2.76 (m, 2H), 2.24 (d,J=1.8 Hz, 3H), 2.00-1.93 (m, 1H), 1.88-1.79 (m, 1H).

Example 275 (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺.¹H NMR (CDCl₃): 7.27-7.22 (m, 2H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 7.03(d, J=2.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.86-6.75 (m, 2H), 4.76 (dd,J=5.7, 4.5 Hz, 1H), 3.01 (d, J=12.8 Hz, 1H), 2.96-2.74 (m, 3H),2.01-1.89 (m, 1H), 1.85-1.71 (m, 1H).

Example 276 (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺.¹H NMR (CDCl₃): 7.21 (t, J=8.1 Hz, 1H), 7.12 (dd, J=8.7, 2.6 Hz, 1H),7.08 (d, J=2.5 Hz, 1H), 7.03 (ddd, J=8.0, 1.9, 0.9 Hz, 1H), 6.89 (d,J=8.7 Hz, 1H), 6.85 (t, J=2.2 Hz, 1H), 6.80 (ddd, J=8.3, 2.4, 0.9 Hz,1H), 4.87-4.51 (m, 1H), 3.00 (d, J=12.8 Hz, 1H), 2.94-2.70 (m, 3H),2.00-1.89 (m, 1H), 1.82-1.71 (m, 1H).

Example 277 (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺.¹H NMR (CDCl₃): 7.43-7.35 (m, 2H), 7.10 (dd, J=8.7, 2.6 Hz, 1H), 7.03(dd, J=8.7, 2.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.80-6.73 (m, 2H), 4.76(dd, J=5.9, 4.4 Hz, 1H), 3.01 (d, J=12.8 Hz, 1H), 2.92 (dt, J=11.4, 7.4Hz, 1H), 2.87-2.72 (m, 2H), 2.02-1.89 (m, 1H), 1.84-1.72 (m, 1H).

Example 278 (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₉H₂₂ClNO₂, 331.1; m/z found, 332.2 [M+H]⁺.¹H NMR (CDCl₃): 7.15 (d, J=8.5 Hz, 2H), 7.07-7.00 (m, 2H), 6.85 (dd,J=11.0, 8.6 Hz, 3H), 4.77 (d, J=4.6 Hz, 1H), 3.04 (d, J=12.8 Hz, 1H),2.92-2.81 (m, 2H), 2.76-2.70 (m, 2H), 1.95-1.87 (m, 1H), 1.82-1.73 (m,1H), 1.24 (d, J=6.9 Hz, 6H).

Example 279(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine

Prepared using 5-bromo-2-(3-bromo-phenoxy)-phenol and(±)-1-ethyl-pyrrolidin-3-ol according to general procedure 7. MS (ESI):mass calcd. for C₁₈H₁₉Br₂NO₂, 439.1; m/z found, 441.0 [M+H]⁺. ¹H NMR(CDCl₃): 7.16-7.12 (m, 2H), 7.08 (dd, J=8.4, 2.2 Hz, 1H), 7.02 (d, J=2.2Hz, 1H), 7.01-6.98 (m, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.87-6.82 (m, 1H),4.74 (m, 1H), 3.02 (dd, J=10.7, 6.2 Hz, 1H), 2.69-2.54 (m, 1H), 2.44 (m,4H), 2.17 (m, 1H), 1.88-1.77 (m, 1H), 1.07 (t, J=7.2 Hz, 3H).

Example 280 2-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone

Step A: Preparation of3-[5-Bromo-2-(hydroxy-phenyl-methyl)-phenoxy]-azetidine-1-carboxylicacid tert-butyl ester

To a solution of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (0.25 g, 0.70 mmol) in CH₂Cl₂ (10 mL) was added asolution of PhMgBr (1M in THF, 1 mL). The reaction was allowed to stirfor 15 h then quenched with 1N HCl (4 mL). After 10 min, the mixture wasmade basic with 1N NaOH (10 mL), and extracted with CH₂Cl₂ (3×20 mL).The organic layers were combined and dried. Chromatography of theresulting residue (SiO₂; EtOAc/Hexanes) gave the title compound (0.24 g,79%). MS (ESI): mass calcd. for C21H₂₄BrNO₄, 433.1; m/z found, 434.4[M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.23 (m, 6H), 7.17 (dd, J=8.2, 1.7, 1 H),6.61 (d, J=1.7, 1 H), 6.04 (s, 1H), 4.90-4.68 (m, 1H), 4.32-4.01 (m,2H), 3.95-3.68 (m, 2H), 2.04-2.10, 1H), 1.44 (s, 9H).

Step B: Preparation of3-(2-Benzoyl-5-bromo-phenoxy)-azetidine-1-carboxylic acid tert-butylester

A solution of the title compound of Step A (0.12 g, 0.28 mmol) andDess-Martin periodane (0.17 g, 0.39 mmol) in CH₂Cl₂ (15 mL) was stirredat rt for 15 h and filtered. The resulting filtrate was concentrated andpurified (SiO₂; EtOAc/Hexanes) providing the title compound (0.10 g,84%). MS (ESI): mass calcd. for C₂₁H₂₂BrNO₄, 431.1; m/z found, 432.4[M+H]⁺. ¹H NMR (CDCl₃): 7.70-7.64 (m, 2H), 7.55-7.45 (m, 1H), 7.40-7.31(m, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.18 (dd, J=8.0, 1.7 Hz, 1H), 6.69 (d,J=1.6 Hz, 1H), 4.72 (tt, J=6.4, 4.2 Hz, 1H), 4.16-3.97 (m, 2H), 3.59(dd, J=10.6, 4.1 Hz, 2H), 1.46-1.25 (m, 9H).

Step C: Preparation of2-(azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone

To a solution of 3-(2-benzoyl-5-bromo-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester (0.10 g, 0.23 mmol) in CH₂Cl₂ (10 mL) was added 2MHCl in Et₂O (0.5 mL). After 15 h, the reaction was concentrated to givethe title compound as the hydrochloride salt which was neutralized with1 N NaOH (5 mL) and extracted with CH₂Cl₂ (3×15 mL). The organic layerswere combined and dried to give the title compound (0.07 g, 90%). MS(ESI): mass calcd. for C₁₆H₁₄BrNO₂, 331.0; m/z found 332.2, [M+H]⁺. ¹HNMR (CD₃OD): 7.82-7.74 (m, 2H), 7.67 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.8Hz, 2H), 7.43-7.32 (m, 2H), 5.47-5.36 (m, 1H), 4.46 (dd, J=12.4, 6.7 Hz,2H), 3.94-3.81 (m, 2H).

Examples 275-292 were synthesized according to Example 274 using theappropriately substituted aryl magnesium halide and aldehyde.

Example 281[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃BrClNO₂, 365.0; m/z found, 366.0 [M+H]⁺.¹H NMR (CD₃OD): 7.91-7.79 (m, 2H), 7.68-7.55 (m, 2H), 7.52-7.41 (m, 2H),5.39-5.26 (m, 1H), 4.65-4.47 (m, 2H), 4.01 (d, J=7.4 Hz, 2H).

Example 282[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃BrClNO₂, 365.0; m/z found, 366.0 [M+H]⁺.¹H NMR (CD₃OD): 7.77 (t, J=1.8, 1 H), 7.71-7.61 (m, 2H), 7.51 (t, J=7.9,1 H), 7.44-7.34 (m, 2H), 7.17 (d, J=1.3, 1H), 5.19 (t, J=4.9, 1 H), 4.45(dd, J=12.7, 6.6, 2H), 3.89 (dd, J=12.6, 4.8, 2H).

Example 283[4-Bromo-2-(1-methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)-methanone

Prepared according to general procedure 5 using the title compound fromExample 276. MS (ESI): mass calcd. for C₁₇H₁₅BrClNO₂, 379.0; m/z found,380.1 [M+H]⁺. ¹H NMR (CD₃OD): 7.74 (t, J=1.7, 1 H), 7.71-7.60 (m, 2H),7.51 (t, J=7.9, 1H), 7.44-7.34 (m, 2H), 7.17 (d, J=1.3, 1H), 5.19 (t,J=4.9, 1H), 4.50-4.40 (m, 2H), 3.90-3.82 (m, 2H). 2.19 (s, 3H).

Example 284 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₂, 345.0; m/z found, 346.1 [M+H]⁺.¹H NMR (CDCl₃): 7.67-7.48 (m, 2H), 7.43-7.13 (m, 4H), 6.90-6.74 (m, 1H),4.98-4.86 (m, 1H), 3.80 (s, 1H), 3.52 (s, 1H), 2.40 (s, 2H), 2.02 (s,3H).

Example 285 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₂, 345.0; m/z found, 346.1 [M+H]⁺.¹H NMR (CDCl₃): 7.46 (d, J=8.2, 1 H), 7.36 (s, 1H), 7.27 (s, 3H),7.23-7.10 (m, 2H), 6.75 (s, 1H), 4.81 (s, 1H), 3.69 (s, 2H), 3.32 (s,2H), 2.44 (s, 3H).

Example 286[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₃, 361.0; m/z found, 362.1 [M+H]⁺.¹H NMR (CDCl₃): 7.39-7.07 (m, 6H), 6.91-6.79 (m, 1H), 4.66 (s, 1H), 3.84(s, 3H), 3.50 (s, 2H), 2.97 (s, 2H).

Example 287[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone

MS (ESI): mass calcd. for C₂₀H₁₆BrNO₂, 381.0; m/z found, 382.1 [M+H]⁺.¹H NMR (CDCl₃): 8.19 (s, 1H), 7.96-7.85 (m, 4H), 7.65-7.50 (m, 2H),7.39-7.21 (m, 2H), 6.85 (d, J=1.6 Hz, 1H), 4.95-4.89 m, 1H), 3.77-3.66(m, 2H), 3.51-3.40 (m, 2H).

Example 288[4-Bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl-methanone

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 281. MS (ESI): mass calcd. for C₂₃H₂₂BrNO₂, 423.1; m/zfound, 426.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.16-8.10 (m, 1H), 7.95-7.85 (m,4H), 7.65-7.50 (m, 2H), 7.39-7.21 (m, 2H), 6.90-6.82 (m, 1H), 4.96-4.80(m, 1H), 3.77-3.66 (m, 2H), 3.51-3.40 (m, 2H), 2.34-2.20 (m, 1H), 0.91(d, J=6.1 Hz, 6H).

Example 289[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1,3]dioxol-5-yl-methanone

MS (ESI): mass calcd. for C₁₇H₁₄BrNO₄, 375.1; m/z found, 376.1 [M+H]⁺.¹H NMR (CDCl₃): 7.38-7.11 (m, 4H), 6.81 (d, J=8.0 Hz, 2H), 6.06 (s, 2H),4.94 (s, 1H), 3.81 (s, 2H), 3.59 (s, 2H).

Example 290Benzo[1,3]dioxol-5-yl-[4-bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 283. MS (ESI): mass calcd. for C₂₀H₂₀BrNO₄, 417.1; m/zfound, 418.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.36-7.15 (m, 4H), 6.76-6.61 (m,2H), 6.06 (d, J=4.1 Hz, 2H), 4.76-4.61 (m, 1H), 3.79-3.63 (m, 2H),2.87-2.75 (m, 2H), 2.34-2.18 (m, 1H), 0.90 (d, J=6.2 Hz, 6H).

Example 291[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₃, 361.0; m/z found, 362.1 [M+H]⁺.¹H NMR (CDCl₃): 7.38-7.12 (m, 6H), 6.96-6.83 (m, 1H), 4.65 (s, 1H), 3.84(s, 3H), 3.54 (s, 2H), 2.99 (s, 2H).

Example 292[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₂BrClFNO₂, 383.0; m/z found, 384.2[M+H]⁺. ¹H NMR (CDCl₃): 7.63-7.40 (m, 3H), 7.38-7.15 (m, 2H), 6.88-6.67(m, 1H), 4.91 (s, 1H), 3.80 (s, 2H), 3.50 (s, 2H).

Example 293[2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₂BrCl₂NO₂, 399.0; m/z found, 400.1[M+H]⁺. ¹H NMR (CDCl₃): 7.83 (d, J=1.9 Hz, 1H), 7.63-7.51 (m, 2H),7.35-7.19 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 5.00-4.85 (m, 1H), 4.02-3.31(m, 4H).

Example 294[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone

MS (ESI): mass calcd. for C₂₀H₁₆ClNO₂, 337.1; m/z found, 338.2 [M+H]⁺.¹H NMR (CDCl₃): 8.19 (s, 1H), 7.98-7.85 (m, 3H), 7.63-7.37 (m, 4H), 7.10(dd, J=8.1, 1.7 Hz, 1H), 6.70 (d, J=1.6 Hz, 1H), 4.97-4.84 (m, 1H), 3.74(s, 2H), 3.50-3.37 (m, 2H).

Example 295[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1,3]dioxol-5-yl-methanone

MS (ESI): mass calcd. for C₁₇H₁₄ClNO₄, 331.1; m/z found, 332.2 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.21 (m, 3H), 7.04 (dd, J=8.1, 1.8 Hz, 1H), 6.82(d, J=8.1 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H), 6.05 (d, J=8.9 Hz, 2H),5.02-4.87 (m, 1H), 3.86 (s, 2H), 3.62 (s, 2H).

Example 296Benzo[1,3]dioxol-5-yl-[4-chloro-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone

Prepared according to general procedure 3 or 4 using the title compoundfrom Example 289. MS (ESI): mass calcd. for C₂₀H₂₀ClNO₄, 373.1; m/zfound, 374.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.40-7.25 (m, 4H), 6.76-6.61 (m,2H), 6.10-6.04 (m, 2H), 4.81-4.64 (m, 1H), 3.75-3.63 (m, 2H), 2.85-2.74(m, 2H), 2.28-2.18 (m, 1H), 0.96 (d, J=6.1 Hz, 6H).

Example 297[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃Cl₂NO₂, 321.0; m/z found, 322.2 [M+H]⁺.¹H NMR (CD₃OD): 7.79-7.62 (m, 2H), 7.56-7.35 (m, 3H), 7.16 (s, 1H),7.00-6.76 (m, 1H), 5.19-5.08 (m, 1H), 4.16 (s, 2H), 3.87 (s, 1H), 3.49(s, 1H).

Example 298[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃Cl₂NO₂, 321.0; m/z found, 322.2 [M+H]⁺.¹H NMR (CDCl₃): 7.70 (t, J=1.7, 1H), 7.62 (dd, J=7.8, 1.3 Hz, 1H),7.58-7.51 (m, 1H), 7.47-7.34 (m, 2H), 7.12 (dd, J=8.2, 1.8 Hz, 1H), 6.61(d, J=1.7 Hz, 1H), 4.87-4.68 (m, 1H), 4.21-4.13 (m, 2H), 3.67 (dd,J=9.9, 4.0 Hz, 2H).

Biological Assays

r5-HT₇ Binding Assay

Receptor binding was performed using membrane fractions prepared fromthe HEK-293 cell line recombinantly expressing rat 5-HT₇ receptors (NCBIaccession NM_(—)022938). Compound affinity for the rat 5-HT₇ receptorsubtype was evaluated by competitive radioligand binding assays using5-carboxamido[³H]tryptamine ([³H]5-CT) (Amersham Biosciences, cat.90000403) detection. HitHunter™ cAMP assays are in-vitro basedcompetitive immunoassays. The assay was performed on the HEK-293 cellline stably transfected with r5-HT₇ receptor. Cells were pre-incubatedwith test compounds for 10 minutes. For antagonist testing, the cellswere then challenged with 100 nM 5-CT for 20 minutes. Cells were thenlysed and cAMP measured according to manufacturers protocol (Amersham,cat. NET791250UC) or [³H]mesulergine (Amersham, cat. TRK1041). The assaywas performed on membranes prepared from HEK-293 cells stablytransfected with h5-HT₆. Following centrifugation, membranes wereresuspended and incubated for 60 min at room temperature with 1.7 nM[³H]LSD in the presence of increasing concentration of test compounds.Nonspecific binding was defined in the presence of 10 μM clozapine(Tocris, cat. TRK1068). Homogenized HEK-293 membranes expressing thehuman SERT were incubated in 50 mM Tris-HCl (pH 7.5), 120 mM NaCl, 5 mMKCl with [³H]-citalopram (3 nM) with or without test compounds.Nonspecific binding was determined in the presence of 10 μM fluoxetine.Radioactivity readouts and K_(i) values were performed as previouslydescribed for r5-HT₇. Table 1 shows assay results for exemplifiedcompounds of the invention. Compounds were assayed in their free form oras salts, as indicated in the Examples section above.

TABLE 1 5HT7- hSERT h5HT6 h5HT2_(A) h5HT2_(B) h5HT2_(C) R5HT7 RATbinding binding binding binding binding cAMP EX. Ki (uM) Ki (uM) K_(i)(uM) K_(i) (uM) K_(i) (uM) K_(i) (uM) pK_(b) 1 0.009 0.048 ND ND ND ND7.9 2 0.012 0.001 0.047 0.042 0.074 0.760 7.5 3 0.018 0.381 ND ND ND ND8.6 4 0.008 ND ND ND ND ND 9.2 5 0.008 0.194 ND ND ND ND 8.3 6 0.0060.249 ND ND ND ND 8.4 7 0.010 0.023 ND ND ND ND 7.2 8 0.006 0.004 ND NDND ND 8.1 9 0.011 0.002 ND ND ND ND 7.7 10 0.007 0.039 0.050 ND ND ND8.2 11 0.053 ND ND ND ND ND ND 12 0.011 0.006 ND ND ND ND 8.5 13 0.0040.006 ND ND ND ND 8.4 14 0.012 0.052 ND ND ND ND 6.8 15 0.017 0.0050.045 ND ND ND 6.2 16 0.100 ND ND ND ND ND ND 17 0.010 0.004 0.039 ND NDND 7.3 18 0.005 0.435 ND ND ND ND 8.8 19 0.004 0.396 ND ND ND ND 8.7 200.008 ND ND ND ND ND ND 21 0.020 ND ND ND ND ND ND 22 0.125 0.028 ND NDND ND ND 23 0.121 ND ND ND ND ND ND 24 0.190 ND ND ND ND ND ND 25 0.0180.019 ND ND ND ND 7.4 26 0.025 0.013 ND ND ND ND ND 27 0.229 1.679 ND NDND ND ND 28 0.049 0.683 ND ND ND ND ND 29 0.083 0.027 ND 0.225 0.5291.109 6.9 30 0.105 ND ND ND ND ND ND 31 0.100 0.090 ND ND ND ND ND 320.053 0.029 ND ND ND ND ND 33 0.007 0.008 ND ND ND ND 7.8 34 0.029 0.001ND ND ND ND 7.4 35 0.023 0.003 ND ND ND ND 6.0 36 0.015 0.036 ND ND NDND 6.1 37 0.008 0.007 0.089 ND ND ND 6.9 38 0.006 0.100 0.036 ND ND ND8.0 39 0.007 0.004 ND ND ND ND 8.5 40 0.009 0.043 ND ND ND ND 7.4 410.130 ND ND ND ND ND ND 42 0.035 0.578 ND ND ND ND ND 43 0.015 0.086 NDND ND ND ND 44 0.087 ND ND ND ND ND ND 45 3.159 0.197 ND ND ND ND ND 460.102 ND ND ND ND ND ND 47 0.011 0.021 ND ND ND ND ND 48 0.088 ND ND NDND ND ND 49 0.013 0.040 ND ND ND ND 7.6 50 0.010 0.005 ND ND ND ND 7.551 0.387 0.086 ND ND ND ND ND 52 0.110 0.089 ND ND ND ND ND 53 0.2600.464 ND ND ND ND ND 54 0.006 0.028 0.077 ND ND ND 8.1 55 0.171 ND ND NDND ND ND 56 8.999 ND ND ND ND ND ND 57 0.042 ND ND ND ND ND ND 58 0.120ND ND ND ND ND ND 59 0.027 0.353 0.084 ND ND ND 7.8 60 0.250 ND ND ND NDND ND 61 0.036 ND ND ND ND ND ND 62 0.034 ND ND ND ND ND ND 63 0.0070.048 ND ND ND ND 7.6 64 0.017 0.043 ND ND ND ND ND 65 0.011 0.014 0.041ND ND ND 6.9 66 0.010 ND ND ND ND ND 7.3 67 0.013 ND ND ND ND ND 6.4 680.017 ND ND ND ND ND 6.2 69 0.094 ND ND ND ND ND ND 70 0.174 ND ND ND NDND ND 71 0.143 ND ND ND ND ND ND 72 0.270 ND ND ND ND ND ND 73 0.0232.177 0.012 ND ND ND 6.6 74 0.011 ND ND ND ND ND ND 75 8.999 ND ND ND NDND ND 76 5.000 ND ND ND ND ND ND 77 0.153 5.000 ND ND ND ND ND 78 0.710ND ND ND ND ND ND 79 0.026 0.003 ND 0.069 0.248 0.290 7.3 80 >10 ND NDND ND ND ND 81 0.097 1.170 ND 0.076 0.367 0.590 ND 82 0.198 ND ND ND NDND ND 83 0.016 0.024 ND ND ND ND ND 84 0.034 0.061 ND ND ND ND ND 850.095 0.404 ND ND ND ND ND 86 0.038 0.121 ND ND ND ND ND 87 0.240 ND NDND ND ND ND 88 0.681 ND ND ND ND ND ND 89 0.025 0.242 ND ND ND ND ND 900.920 ND ND 0.020 0.083 0.160 ND 91 0.500 ND ND 0.005 0.050 0.120 ND 920.260 ND ND 0.014 0.028 0.110 ND 93 0.140 ND ND 0.003 0.013 0.051 ND94 >2.499 ND ND 0.032 0.250 0.069 ND 95 0.009 ND ND ND ND ND ND 96 0.013ND ND ND ND ND ND 97 0.034 ND ND ND ND ND ND 98 0.023 ND ND ND ND ND ND99 0.005 ND ND ND ND ND ND 100 0.150 ND ND ND ND ND ND 101 0.005 0.1520.746 0.317 0.203 0.933 ND 102 0.376 0.954 ND ND ND ND ND 103 0.027 NDND ND ND ND ND 104 0.166 ND ND ND ND ND ND 105 0.023 0.193 ND ND ND ND7.3 106 0.075 ND ND ND ND ND ND 107 0.090 ND ND ND ND ND ND 108 0.0365    ND ND ND ND ND 109 0.005 2.900 ND ND ND ND ND 110 0.090 0.554 ND NDND ND ND 111 0.010 0.118 0.268 0.073 0.069 0.331 ND 112 0.023 0.138 NDND ND ND 7.5 113 0.011 0.058 0.496 0.206 0.122 0.490 ND 114 0.014 0.075ND ND ND ND 7.5 115 0.033 0.202 ND ND ND ND ND 116 0.068 ND ND ND ND NDND 117 0.041 0.071 ND ND ND ND ND 118 0.090 ND ND ND ND ND ND 119 0.288ND ND ND ND ND ND 120 0.040 ND ND ND ND ND ND 121 0.033 0.164 ND ND NDND ND 122 0.210 ND ND ND ND ND ND 123 0.042 0.025 ND ND ND ND ND 1240.043 0.020 ND ND ND ND ND 125 0.104 ND ND ND ND ND ND 126 0.038 ND NDND ND ND ND 127 0.063 ND ND ND ND ND ND 128 0.127 ND ND ND ND ND ND 1290.903 ND ND ND ND ND ND 130 0.371 ND ND ND ND ND ND 131 0.073 1.355 NDND ND ND ND 132 0.456 ND ND ND ND ND ND 133 0.591 ND ND ND ND ND ND 1343.827 ND ND ND ND ND ND 135 0.015 0.096 1.275 0.140 0.027 0.755 ND 1360.029 0.098 ND ND ND ND ND 137 0.472 ND ND ND ND ND ND 138 0.042 ND NDND ND ND ND 139 0.189 ND ND ND ND ND ND 140 0.230 ND ND ND ND ND ND 1410.450 ND ND ND ND ND ND 142 0.091 0.613 ND ND ND ND ND 143 0.215 ND NDND ND ND ND 144 0.304 ND ND ND ND ND ND 145 0.040 0.773 ND ND ND ND ND146 0.012 0.059 0.558 ND ND ND 8.1 147 0.211 ND ND ND ND ND ND 148 2.000ND ND ND ND ND ND 149 >10 ND ND ND ND ND ND 150 0.010 0.013 ND ND ND ND8.0 151 0.040 ND ND ND ND ND 7.5 152 0.019 0.025 ND ND ND ND 7.4 1530.084 ND ND ND ND ND 7.2 154 0.018 0.013 ND ND ND ND 7.7 155 0.019 0.045ND ND ND ND ND 156 0.252 ND ND ND ND ND <5   157 0.010 0.181 ND ND ND ND8.3 158 0.015 0.067 ND 0.008 0.036 0.146 8.0 159 0.017 0.021 ND 0.0060.041 0.196 8.1 160 0.015 0.210 ND 0.005 0.025 0.146 8.3 161 0.028 0.060ND ND ND ND 7.8 162 5.000 ND ND ND ND ND ND 163 0.766 ND ND ND ND ND ND164 0.033 0.008 ND 0.024 0.030 0.181 ND 165 0.016 0.095 ND ND ND ND ND166 1.269 ND ND ND ND ND ND 167 0.167 ND ND ND ND ND ND 168 0.130 ND ND0.008 0.021 0.048 ND 169 0.119 ND ND ND ND ND ND 170 5.000 ND ND ND NDND ND 171 0.007 0.234 ND ND ND ND ND 172 5.000 ND ND ND ND ND ND 1730.007 0.056 ND ND ND ND 8.1 174 0.006 0.042 ND ND ND ND 8.2 175 0.0110.004 ND ND ND ND ND 176 0.024 0.075 ND ND ND ND ND 177 0.012 0.2620.123 0.035 0.056 0.140 ND 178 0.017 0.131 ND ND ND ND ND 179 0.360 NDND ND ND ND ND 180 0.813 ND ND ND ND ND ND 181 0.019 0.967 ND ND ND ND7.7 182 0.076 0.514 ND ND ND ND ND 183 0.110 ND ND ND ND ND ND 184 0.0230.124 ND 0.005 0.012 0.038 7.3 185 0.006 0.029 0.177 0.008 0.007 0.091ND 186 0.005 0.053 0.033 0.014 0.008 0.079 ND 187 0.036 0.340 ND ND NDND ND 188 0.034 0.065 ND 0.008 0.028 0.143 ND 189 0.138 ND ND ND ND NDND 190 0.008 0.211 ND 0.014 0.069 0.056 ND 191 0.008 0.007 ND 0.0080.011 0.053 ND 192 0.008 0.088 ND 0.009 0.022 0.140 ND 193 0.005 0.009ND 0.011 0.014 0.071 ND 194 0.004 0.141 ND 0.004 0.195 0.081 ND 1950.002 0.060 0.027 0.010 0.004 0.042 ND 196 0.359 0.053 ND ND ND ND ND197 1.421 ND ND ND ND ND ND 198 1.462 ND ND ND ND ND ND 199 0.018 0.128ND 0.103 1.223 0.526 7.4 200 0.031 0.224 ND 0.605 7.568 5.000 6.8 2010.031 0.056 ND 0.067 0.184 0.498 7.3 202 0.066 ND ND ND ND ND ND 2030.024 0.271 ND ND ND ND 7.7 204 0.027 ND ND ND ND ND ND 205 0.027 ND NDND ND ND ND 206 0.021 ND ND ND ND ND ND 207 0.020 ND ND ND ND ND 7.8 2080.365 0.303 ND ND ND ND ND 209 0.013 0.020 ND ND ND ND 7.7 210 0.506 NDND ND ND ND ND 211 8.999 ND ND ND ND ND ND 212 0.053 0.041 ND ND ND NDND 213 4.589 ND ND ND ND ND ND 214 8.999 1.693 ND ND ND ND ND 215 0.0110.044 ND 0.006 0.017 0.026 ND 216 0.016 0.036 ND ND ND ND ND 217 0.0340.113 ND ND ND ND ND 218 0.069 ND ND ND ND ND ND 219 0.009 0.068 ND NDND 0.031 ND 220 0.493 0.789 ND ND ND ND ND 221 0.147 5    ND ND ND ND ND222 0.018 2.114 ND ND ND 1.009 ND 223 0.145 8.999 ND ND ND ND ND 2240.068 ND ND ND ND ND ND 225 2.669 ND ND ND ND ND ND 226 0.840 ND ND NDND ND ND 227 0.336 ND ND ND ND ND ND 228 0.009 0.072 ND ND ND ND ND 2290.003 0.925 ND ND ND ND ND 230 0.006 1.203 ND ND ND ND ND 231 0.0154.481 ND ND ND ND ND 232 0.003 0.001 ND ND ND ND ND 233 0.027 0.023 NDND ND ND ND 234 0.130 ND ND ND ND ND ND 235 0.665 ND ND ND ND ND ND 2360.831 ND ND ND ND ND ND 237 0.120 ND ND ND ND ND ND 238 0.200 ND ND NDND ND ND 239 0.233 ND ND ND ND ND ND 240 0.252 ND ND ND ND ND ND 2410.263 ND ND ND ND ND ND 242 0.273 ND ND ND ND ND ND 243 0.461 ND ND NDND ND ND 244 0.020 5.000 0.046 ND ND ND 6.6 245 0.009 ND ND ND ND ND 6.7248 0.043 ND ND ND ND ND ND 249 0.020 ND ND ND ND ND ND 250 0.017 ND NDND ND ND ND 251 0.011 ND ND ND ND ND 6.8 252 0.007 0.060 ND ND ND ND 7.2253 0.018 ND ND ND ND ND 6.3 254 0.019 ND ND ND ND ND ND 255 0.196 ND NDND ND ND ND 256 0.160 ND ND ND ND ND ND 257 0.021 ND ND ND ND ND 6.3 2580.023 ND ND ND ND ND 6.3 259 0.460 ND ND ND ND ND ND 260 0.016 0.002 NDND ND ND 6.0 261 1.604 ND ND ND ND ND ND 262 0.031 0.112 ND ND ND ND ND263 0.544 ND ND ND ND ND ND 264 1.097 ND ND ND ND ND ND 265 0.130 ND NDND ND ND ND 266 >10 ND ND 0.150 0.130 0.230 ND 267 2.300 ND ND 0.1200.065 0.210 ND 268 0.820 ND ND 0.150 0.130 0.380 ND 269 >10 ND ND 0.1900.500 0.400 ND 270 1.000 ND ND 0.120 0.075 0.240 ND 271 0.660 ND ND0.078 0.098 0.350 ND 272 >10 ND ND 0.220 0.310 0.330 ND 273 >5 ND ND0.082 0.160 0.150 ND 274 8.600 ND ND 0.100 0.170 0.230 ND 275 >10 ND ND0.530 0.910 0.220 ND 276 >10 ND ND 0.084 0.190 0.120 ND 277 5.500 ND ND0.410 0.270 0.120 ND 278 >10 ND ND 1.400 1.300 0.330 ND 279 0.025 ND NDND ND ND ND 280 0.098 ND ND ND ND ND ND 281 0.048 ND ND ND ND ND 6.5 2820.039 ND ND ND ND ND 6.7 283 0.050 ND ND ND ND ND ND 284 0.019 ND ND NDND ND ND 285 3.000 ND ND ND ND ND ND 286 0.039 ND ND ND ND ND ND 2870.015 0.014 ND ND ND ND 7.2 288 0.059 ND ND ND ND ND ND 289 0.034 0.437ND ND ND ND 7.4 290 0.143 ND ND ND ND ND ND 291 0.034 ND ND ND ND ND ND292 0.074 ND ND ND ND ND ND 293 0.051 ND ND ND ND ND ND 294 0.072 ND NDND ND ND ND 295 0.226 ND ND ND ND ND ND 296 0.181 ND ND ND ND ND ND 2970.150 ND ND ND ND ND ND 298 0.102 ND ND ND ND ND ND *ND symbolizes notdetermined.

While the invention has been illustrated by reference to exemplary andpreferred embodiments, it will be understood that the invention isintended not to be limited by the foregoing detailed description, but tobe defined by the appended claims as properly construed under principlesof patent law.

What is claimed is:
 1. A compound selected from the group consisting of(a) compounds of Formula (I):

wherein R¹ is —H, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl;m is 1; n is 2; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is—H, F, C₁₋₄alkyl, or R⁴ is —OH when L is —CH₂—, —CF₂—, —CHF—, —OCH₂—, or—OCH(CH₃)—; L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or—CHF—; Z is —O—, —C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—; whereR^(b) is —H; a —C₁₋₄alkyl group unsubstituted or substituted with OH orhalo; —CO₂C₁₋₄alkyl; or —CO₂H; and R^(c) and R^(d) are eachindependently —H, —C₁₋₄alkyl, —O—C₁₋₄alkyl, or halo; or R^(c) and R^(d)taken together form an oxime, a C₁₋₄alkyl oxime, or a carbonyl group; orR^(c) and R^(d) taken together with the carbon to which they areattached form a C₃₋₆cycloalkyl group; R⁵ is: i) a phenyl group,unsubstituted or substituted with one, two, or three R^(g) substituents;where each R^(g) substituent is selected from the group consisting of:—C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃,—OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl,thiophenyl, benzhydryl, and oxadiazolyl; or two R^(g) substituents takentogether form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O—; ii) a naphthyl group,unsubstituted or substituted with C₁₋₄alkyl or halo; iii) a monocyclicheteroaryl group, unsubstituted or substituted with one, two, or threeR^(g) substituents; iv) a fused bicyclic heteroaryl group, unsubstitutedor substituted with C₁₋₄alkyl or halo; v) a monocyclic cycloalkyl group,optionally fused to a phenyl ring, and unsubstituted or substituted withone or two substituents selected from the group consisting of:—C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime, —C₁₋₄alkyl oxime, or phenyl;or vi) a monocyclic heterocycloalkyl group, optionally fused to orsubstituted with phenyl; X is C or N; R⁶ or R⁷ are each independently—H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y); wherein R^(x) andR^(y) are each independently —H or —C₁₋₄alkyl; and (b) pharmaceuticallyacceptable salts of the compounds of Formula (I).
 2. A compound asdefined in claim 1, wherein R¹ is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —C(CH₃)₃, cyclopropyl, cyclobutyl, or benzyl.
 3. A compoundas defined in claim 2, wherein R¹ is —H.
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. A compound as defined in claim 1, wherein R²is —H or —CH₃.
 9. A compound as defined in claim 1, wherein R³ is —H or—CH₃.
 10. A compound as defined in claim 1, wherein R² and R³ are each—H.
 11. A compound as defined in claim 1, wherein R⁴ is —H.
 12. Acompound as defined in claim 1, wherein L is —O—, —CH₂—, —OCH₂—,—OCH(CH₃)—, —CH₂O—, —CHF—, or —CF₂—.
 13. A compound as defined in claim1, wherein L is —O—.
 14. A compound as defined in claim 1, wherein Z is—O—, —C(O)—, —OCH₂—, —OCH(CH₃)—, —OCH(CH₂CH₃)—, —OCH(CH₂OH)—,—OCH(CO₂H)—, —OCH(CH₂F)—, —OCH₂CH₂—, —OCH₂CH(F)—, —OCH₂CH(OCH₃)—,—OCH₂C(NOH)—, —OCH₂C(NOCH₃)—, —OCH₂CF₂—, —OCH₂C(O)—, or


15. A compound as defined in claim 1, wherein Z is —O—, —OCH₂—,—OCH₂CH₂—, or —OCH(CH₃)—.
 16. A compound as defined in claim 1, whereinR⁵ is phenyl, optionally substituted with halo, —OCH₃, —OSO₂CH₃, CF₃,


17. A compound as defined in claim 1, wherein R⁵ is cyclohexyl,2-indanyl, or furanyl optionally substituted with one or moresubstituents individually selected from halo, —CH₃, —CF₃, —OCF₃, or —CN.18. A compound as defined in claim 1, wherein R⁵ is selected from thegroup consisting of: i) cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl,cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl,2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3-or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl,3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl,3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl,4-fluoro-3-trifluoromethyl-phenyl, 3- or4-trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-phenyl,

 and ii) 3-azetidinyl, 1-benzyl-azetidin-3-yl,1-benzhydryl-azetidin-3-yl, 1-isopropyl-azetidin-3-yl,benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl,2-benzofuranyl, 5-benzofuranyl, 2,3-dihydro-benzofuran-2-yl,2-benzothiazolyl, 6-benzothiazolyl, 1H-benzotriazole-6-yl,1-methyl-1H-benzotriazole-6-yl, 2- or 3-chromanyl, 2- or 3-furanyl,5-trifluoromethyl-2-furanyl, 2-indanyl, tetrahydro-3-furanyl,1-Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl, 5-fluoro-1-indanyl,5-methyl-1-indanyl, 5- or 6-chloro-1-indanyl, 6-fluoro-1-indanyl,6-trifluoromethyl-1-indanyl, 6-methyl-1-indanyl, 5-fluoro-2-indanyl,5-methoxy-2-indanyl, [1,2,4]oxadiazole-5-yl,3-cyclopropyl-[1,2,4]oxadiazole-5-yl,3-cyclobutyl-[1,2,4]oxadiazole-5-yl, 3-isopropyl-[1,2,4]oxadiazole-5-yl,phenoxy, 4-piperidinyl, 2- or 3-pyrrolidinyl,3-methyl-[1,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl,4-trifluoromethyl-2-pyridinyl, 2-, 3- or 4-pyridinyl,6-trifluoromethyl-2-pyridinyl, 1,2,3,4-tetrahydro-naphthalen-1-yl,1,2,3,4-tetrahydro-naphthalen-2-yl, 1-phenyl-3-azetidinyl, 4- or5-thiazolyl, 2-methyl-thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl,

 5-methyl-isoxazole-3-yl.
 19. A compound as defined in claim 1, whereinR⁶ and R⁷ are each independently —H, halo, —CF₃, thiophene-3-yl, orN,N-dimethyl-formamidyl.
 20. A compound as defined in claim 1, whereinR⁶ is —H or halo.
 21. A compound as defined in claim 1, wherein R⁶ is —Hor halo and R⁷ is —H, halo, —CF₃, thiophene-3-yl, orN,N-dimethyl-formamidyl.
 22. (canceled)
 23. (canceled)
 24. A compound asdefined in claim 1, selected from the group consisting of:(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;(±)-Methanesulfonic acid3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;(±)-Methanesulfonic acid3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine;(S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; andpharmaceutically acceptable salts thereof.
 25. A pharmaceuticalcomposition, comprising an effective amount of at least one compoundselected from compounds of Formula (I):

wherein R¹ is —H, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl;m is 1; n is 2; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is—H, F, C₁₋₄alkyl, or R⁴ is —OH when L is —CH₂—, —CF₂—, —CHF—, —OCH₂—, or—OCH(CH₃)—; L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or—CHF—; Z is —O—, —C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—; whereR^(b) is —H; a —C₁₋₄alkyl group unsubstituted or substituted with OH orhalo; —CO₂C₁₋₄alkyl; or —CO₂H; and R^(c) and R^(d) are eachindependently —H, —C₁₋₄alkyl, —O—C₁₋₄alkyl, or halo; or R^(c) and R^(d)taken together form an oxime, a C₁₋₄alkyl oxime, or a carbonyl group; orR^(c) and R^(d) taken together with the carbon to which they areattached form a C₃₋₆cycloalkyl group; R⁵ is: i) a phenyl group,unsubstituted or substituted with one, two, or three R^(g) substituents;where each R^(g) substituent is selected from the group consisting of:—C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃,—OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl,thiophenyl, benzhydryl, and oxadiazolyl; or two R^(g) substituents takentogether form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O—; ii) a naphthyl group,unsubstituted or substituted with C₁₋₄alkyl or halo; iii) a monocyclicheteroaryl group, unsubstituted or substituted with one, two, or threeR^(g) substituents; iv) a fused bicyclic heteroaryl group, unsubstitutedor substituted with C₁₋₄alkyl or halo; v) a monocyclic cycloalkyl group,optionally fused to a phenyl ring, and unsubstituted or substituted withone or two substituents selected from the group consisting of:—C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime, —C₁₋₄alkyl oxime, or phenyl;and vi) a monocyclic heterocycloalkyl group, optionally fused to orsubstituted with phenyl; X is C or N; R⁶ or R⁷ are each independently—H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y); wherein R^(x) andR^(y) are each independently —H or —C₁₋₄alkyl; and (b) pharmaceuticallyacceptable salts of the compounds of Formula (I).
 26. A pharmaceuticalcomposition according to claim 25, wherein said at least one compound isselected from the group consisting of:(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;(R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;(R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(3-chloro-benzoyloxy)-phenoxy]-1-methyl-pyrrolidine;(S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;(±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-methyl-pyrrolidine;(±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;(±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;(±)-Methanesulfonic acid3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;(±)-Methanesulfonic acid3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;(S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;(R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;(S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;(R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;(S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;(S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;(S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;(S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]pyrrolidine;(S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and(±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; andpharmaceutically acceptable salts thereof.
 27. A pharmaceuticalcomposition according to claim 25, further comprising: an activeingredient selected from the group consisting of an additional activeingredient selected from the group consisting of: H₁ receptorantagonists, H₂ receptor antagonists, H₃ receptor antagonists,topiramate, norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors, noradrenergic reuptake inhibitors, non-selectiveserotonin re-uptake inhibitors, acetylcholinesterase inhibitors,modafinil, anti-psychotics, sedatives, monoamine oxidase inhibitors, andtricyclic antidepressants.
 28. A method of treating a subject sufferingfrom or diagnosed with a disease, disorder, or condition mediated by5HT₇ activity, comprising administering to the subject an effectiveamount of at least one agent selected from compounds of Formula (I):

wherein R¹ is —H, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl;m is 1; n is 2; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is—H, F, C₁₋₄alkyl, or R⁴ is —OH when L is —CH₂—, —CF₂—, —CHF—, —OCH₂—, or—OCH(CH₃)—; L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or—CHF—; Z is —O—, —C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—; whereR^(b) is —H; a —C₁₋₄alkyl group unsubstituted or substituted with OH orhalo; —CO₂C₁₋₄alkyl; or —CO₂H; and R^(c) and R^(d) are eachindependently —H, —C₁₋₄alkyl, —O—C₁₋₄alkyl, or halo; or R^(c) and R^(d)taken together form an oxime, a C₁₋₄alkyl oxime, or a carbonyl group; orR^(c) and R^(d) taken together with the carbon to which they areattached form a C₃₋₆cycloalkyl group; R⁵ is: i) a phenyl group,unsubstituted or substituted with one, two, or three R^(g) substituents;where each R^(g) substituent is selected from the group consisting of:—C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃,—OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl,thiophenyl, benzhydryl, and oxadiazolyl; or two R^(g) substituents takentogether form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O—; ii) a naphthyl group,unsubstituted or substituted with C₁₋₄alkyl or halo; iii) a monocyclicheteroaryl group, unsubstituted or substituted with one, two, or threeR^(g) substituents; iv) a fused bicyclic heteroaryl group, unsubstitutedor substituted with C₁₋₄alkyl or halo; v) a monocyclic cycloalkyl group,optionally fused to a phenyl ring, and unsubstituted or substituted withone or two substituents selected from the group consisting of:—C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime, —C₁₋₄alkyl oxime, or phenyl;and vi) a monocyclic heterocycloalkyl group, optionally fused to orsubstituted with phenyl; X is C or N; R⁶ or R⁷ are each independently—H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y); wherein R^(x) andR^(y) are each independently —H or —C₁₋₄alkyl; and (b) pharmaceuticallyacceptable salts of the compounds of Formula (I).
 29. A method accordingto claim 28, wherein the disease, disorder, or condition is selectedfrom the group consisting of: sleep disorders, depression/anxiety,generalized anxiety disorder, schizophrenia, bipolar disorders,cognitive disorders, mild cognitive impairment, Alzheimer's disease,Parkinson's disease, psychotic disorders, phobic disorders,obsessive-compulsive disorder, mood disorders, post-traumatic stress andother stress-related disorders, migraine, pain, eating disorders,obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance,hot flushes associated with menopause, alcohol abuse, drug abuse,addictive disorders including drug addiction and alcohol addiction,nausea, inflammation, centrally mediated hypertension, sleep/wakedisturbances, jetlag, and circadian rhythm abnormalities.
 30. A methodaccording to claim 28, wherein the disease, disorder, or condition isselected from the group consisting of: hypotension, peripheral vasculardisorders, cardiovascular shock, renal disorders, gastric motility,diarrhea, spastic colon, irritable bowel disorders, ischemias, septicshock, and urinary incontinence.
 31. The method according to claim 28,wherein the disease, disorder, or medical condition is selected from thegroup consisting of: glaucoma, optic neuritis, diabetic retinopathy,retinal edema, and age-related macular degeneration.